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 Obesity
Genomics and
Postgenomics

Clement_978-0849380891_TP.indd 1 8/8/07 11:34:08 AM

 Obesity
Genomics and
Postgenomics

Edited by
Karine Clément
Pitié-Salpêtrière Hospital
Paris, France

Thorkild I.A. Sørensen

Institute of Preventive Medicine
Copenhagen University Hospitals
Copenhagen, Denmark

Clement_978-0849380891_TP.indd 2 8/8/07 11:34:09 AM

Informa Healthcare USA, Inc.
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© 2008 by Informa Healthcare USA, Inc.

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International Standard Book Number-10: 0-8493-8089-8 (Hardcover)
International Standard Book Number-13: 978-0-8493-8089-1 (Hardcover)
This book contains information obtained from authentic and highly regarded sources. Reprinted
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listed. Reasonable efforts have been made to publish reliable data and information, but the author
and the publisher cannot assume responsibility for the validity of all materials or for the
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Library of Congress Cataloging-in-Publication Data

Library of Congress Cataloging-in-Publication Data
Obesity: genomics and postgenomics / edited by Karine Clément,
Thorkild I.A. Sørensen.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-0-8493-8089-1 (hardcover : alk. paper)
ISBN-10: 0-8493-8089-8 (hardcover : alk. paper) 1. Obesity–Genetic aspects.
I. Clément, Karine, 1966- II. Sørensen, Thorkild I. A.
[DNLM: 1. Obesity–genetics. WD 210 G3281 2007]

RC628.G47 2007
616.3'98042–dc22 2007015263

Visit the Informa web site at

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For Professor Albert J. Strunkard
—T.I.A. Sørensen

For Professor Daniel Ricquier

—K. Clément
 Preface

The understanding of how genes influence the development and maintenance of

obesity and its complications, such as type 2 diabetes and cardiovascular disease,
has increased dramatically in recent decades, not in the least due to the develop-
ment of tools for investigating genes and gene functions (i.e., large-scale genome
screening). However, there is still much to learn. During this period several books
on this topic have been published, but advances have been so rapid that a new
one offering an updated overview of where we are now, the current front line
questions, the technology that may help answer the questions, as well as future
challenges and opportunities, is justified.
For some years, an annually updated comprehensive catalogue of findings
on the genetics of obesity, defined as the role of interindividual genetic variation,
has been published under the name, “The Obesity Gene Map,” and the informa-
tion it contains has been compiled in a useful website (www.obesitygene.pbrc.
edu). However, for researchers and teachers approaching this field, there is a need
to combine this source with an overview of the genomics of obesity, by which we
mean the study of gene functions, the regulation of gene functions, and down-
stream relationships, including the interaction with environmental exposures in
the broadest sense. Insight into possibilities and limitations is also needed to
achieve a reasonable understanding of the current status and progress in the field.
We have attempted to cover all the relevant main topics in the study of the
genomics of human obesity, which clearly must also include rodent and non-
vertebrate research. We have included both phenotypic quantitative genetics and
molecular genetics, and we have added epigenetics and postgenomic processes, in
addition to genotype-phenotype relationships.
On the other hand, the book does not intend to provide a completely up-to-
date and comprehensive picture of the field. In view of the time it takes to
produce a book and the amount of information emerging almost daily from many
different laboratories, this would not be feasible. Since we began working on the
book, several new discoveries have been made, and new technologies have come
to prevailing use. A good example is the recent discovery, in a genome-wide
search for genes associated with type 2 diabetes, of a very strong statistical
association between a common, single nucleotide polymorphism in the FTO gene
and the level of body mass index in the general population, published just before
the final typesetting (www.scienceexpress.org 12 April, 2007). Aiming to incorpo-
rate each new important finding and technological development would make the
writing of the book a never-ending story.
Our intention is rather to present a series of chapters in which competent
and experienced experts, still actively involved in research in the field, give their
current view on the topic of the chapter they were assigned to write. We have
given contributors the freedom to set their own priorities in what and how they
want to present their material within each chapter, with no editorial interference.
This has a number of important implications for the reader. First, each chapter

v
vi Preface

may be read as if it is an independent review article; second, there may well be

repetition and even discordance among chapters, reflecting the diversity of
opinions on the same issues; third, the selection of references in each chapter is
based on what the contributors feel represents the core literature on the particular
topic; fourth, the editors may not always share the opinions of the authors on
various issues. The terminology and abbreviations used also reflect current
customs in a particular area, except that we have used gene and gene product
names and abbreviations in accordance with international standards.

ACKNOWLEDGMENT
The authors would also like to thank Ms. Catherine Couton for her excellent
technical work in formatting the chapters.

Karine Clément
Thorkild I.A. Sørensen
 Contents

Preface v
Contributors xi
Introduction xvii

Section 1: Obesity Phenotype

1.1. Human Phenotypes 1
Jean-Michel Oppert, Martine Laville, and Arnaud Basdevant
Section 2: Quantitative Genetics of Obesity
2.1. Family Studies 19
Finn Rasmussen, Patrik K.E. Magnusson, and Thorkild I.A. Sørensen
2.2. Adoption Studies 29
Thorkild I.A. Sørensen, Finn Rasmussen, and Patrik K.E. Magnusson
2.3. Twin Studies 39
Jaakko Kaprio and Jennifer R. Harris
2.4. Experimental Twin Studies 49
Claude Bouchard and Tuomo Rankinen
2.5. Commingling and Segregation Analyses 59
Treva Rice
Section 3: Rodent Models of Obesity
3.1. Natural Monogenic Models 77
Allison W. Xu, Andrew A. Butler, and Gregory S. Barsh
3.2. Transgenic Models Targeting the Central Nervous System 89
James L. Trevaskis, Gregory M. Sutton, Allison W. Xu, and
Andrew A. Butler
3.3. Transgenic Models in the Periphery 109
Isabelle Castan-Laurell, Jérémie Boucher, Cédric Dray, and Philippe Valet
3.4. Natural Polygenic Models 125
Daniel Pomp
Section 4: Nonvertebrate Models
4.1. Will Fatty Worms or Flies Help Discover the Mechanism of Human
Obesity? 143
Sona Kang, Vernon Dolinsky, and Ormond A. MacDougald

vii
viii Contents

Section 5: Syndromic and Monogenic Human Obesity

5.1. Overview of Human Monogenic, Nonsyndromic, and Syndromic Obesity 157
Wendy K. Chung and Rudolph L. Leibel
5.2. Prader-Willi Syndrome 179
Oenone Dudley and Françoise Muscatelli
5.3. Bardet-Biedl Syndrome: New Insights into Ciliopathies and
Oligogenic Traits 195
Hélène Dollfus, Philip Beales, and Nicholas Katsanis
5.4. Leptin and Leptin Receptor Mutations 205
I. Sadaf Farooqi and Stephen O’Rahilly
5.5. POMC and PC1 Mutations 213
I. Sadaf Farooqi and Stephen O’Rahilly
5.6. MC4R Mutations 221
Cécile Lubrano-Berthelier and Christian Vaisse
Section 6: Polygenic Human Obesity
6.1. Overview of Genetic Studies in Polygenic Obesity and Methodological
Challenges 229
David T. Redden, Jasmin Divers, Laura K. Vaughan, Miguel Padilla,
Solomon Musani, Hemant K. Tiwari, and David B. Allison
6.2. Genome-Wide Approaches 247
Jorg Hager, Elke Roschman, David Mutch, and Karine Clément
6.3. Association and Linkage Studies in Caucasians 255
Anke Hinney and Johannes Hebebrand
Section 7: Gene-Environment Interaction in Human Obesity
7.1. Genetics of Eating Behavior 265
Antonio Tataranni and Monica Bertolini
7.2. Genetics of Physical Activity 277
Tuomo Rankinen and Claude Bouchard
7.3. Interaction Between Genes and Lifestyle Factors 287
Ruth J.F. Loos, Karani S. Vimaleswaran, and Nicholas J. Wareham
7.4. Genetics and Hormonal Changes 327
Roland Rosmond
7.5. Genetics and Drugs 337
Yvon C. Chagnon, Paola Artioli, and Alessandro Serretti
Section 8: Epigenetics in Obesity
8.1. Molecular Basis of Epigenetic Memory 347
C. Gallou-Kabani, A. Vigé, M.S. Gross, and C. Junien
8.2. Implications for Obesity and Common Diseases 365
C. Gallou-Kabani, A. Vigé, M.S. Gross, and C. Junien
Contents ix

Section 9: Tissue and Organ-Specific Gene Function

9.1. Genes Regulating Adipose-Tissue Development and Function 407
Sven Enerbäck
9.2. Genetics of Adipose-Tissue Development and Function in Humans 413
Ingrid Dahlman and Peter Arner
9.3. Nutritional Regulation of Adipocyte Differentiation 429
Lise Madsen, Rasmus Koefoed Petersen, and Karsten Kristiansen
9.4. Genes Involved in Muscle Function 451
Béatrice Morio, Stéphane Walrand, and Yves Boirie
9.5. Genes Involved in Gut and Brain Dialogue 461
Philip Just Larsen and Jens Juul Holst
Section 10: Omics Technology and System Biology
10.1. Introduction to Omics Platforms 473
Martin Kussmann, Frédéric Raymond, and Michael Affolter
10.2. Analysis and Data Integration 491
R. Keira Curtis, Antonio Vidal-Puig, and Matej Oresic
10.3. Transcriptomics Results 513
Frédéric Capel, Dominique Langin, Hubert Vidal, and Karine Clément
10.4. Proteomics and Metabonomics Routes Toward Obesity 527
Martin Kussmann and Michael Affolter
10.5. Quantitative Proteomics for Analysis of Adipocyte Development
and Function 537
Ariane Minet, Karsten Kristiansen, and Irina Kratchmarova
Section 11: Conclusion
11.1. Exciting Advances and New Opportunities 549
Claude Bouchard and Tuomo Rankinen

Index 563
 Contributors

Michael Affolter Functional Genomics Group, Bioanalytical Science Department,

Nestlé Research Center, Lausanne, Switzerland
David B. Allison Section on Statistical Genetics, Department of Biostatistics,
University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
Peter Arner Karolinska Institutet, Department of Medicine, Karolinska University
Hospital-Huddinge, Stockholm, Sweden
Paola Artioli Department of Psychiatry, San Raffaele Institute, Milan, Italy
Gregory S. Barsh Department of Genetics, Stanford University School of Medicine,
Stanford, California, U.S.A.
Arnaud Basdevant INSERM, U872, Nutriomique, Centre de Recherche des
Cordeliers, Université Pierre et Marie Curie-Paris6, UMRS 872, Université Paris
Descartes, Assistance Publique Hôspitaux de Paris, AP-HP, and Department of
Endocrinology and Nutrition, Pitié-Salpêtrière Hospital, Paris, France
Philip Beales Molecular Medicine Unit, UCL Institute of Child Health, London, U.K.
Monica Bertolini Cattedra e Servizio di Endocrinologia e malattie del metabolismo,
University degli Studi di Modena e Reggio Emilia, Modena, Italy
Yves Boirie INRA, UMR 1019, Université de Clermont-Ferrand, Auvergne and
Unité de Nutrition Humaine, Clermont-Ferrand, France
Claude Bouchard Human Genomics Laboratory, Pennington Biomedical Research
Center, Baton Rouge, Louisiana, U.S.A.
Jérémie Boucher INSERM, U858, Institut de Médecine Moléculaire de Rangueil and
Institut Louis Bugnard, Université Paul Sabatier, Toulouse, France
Andrew A. Butler Pennington Biomedical Research Center, Louisiana State
University System, Baton Rouge, Louisiana, U.S.A.
Frédéric Capel INSERM, U858, Laboratoire de Recherches sur les Obésités, Institut
de Médecine Moléculaire de Rangueil, Institut Louis Bugnard IFR 31, Université Paul
Sabatier, and Centre Hospitalier, Universitaire de Toulouse, Toulouse, France
Isabelle Castan-Laurell INSERM, U858, Institut de Médecine Moléculaire de
Rangueil and Institut Louis Bugnard, Université Paul Sabatier, Toulouse, France
Yvon C. Chagnon Psychiatric Genetic Unit, Laval University Research Center
Robert-Giffard, Beauport, Quebec, Canada
Wendy K. Chung Division of Molecular Genetics and The Naomi Berrie Diabetes
Center, Columbia University Medical College, New York, New York, U.S.A.
Karine Clément INSERM, U872, Nutriomique, Centre de Recherche des Cordeliers,
Université Pierre et Marie Curie-Paris6, UMRS 872, Université Paris Descartes,
Assistance Publique Hôpitaux de Paris, AP-HP, and Department of Endocrinology and
Nutrition, Pitié-Salpêtrière Hospital, Paris, France

xi
xii Contributors

R. Keira Curtis Department of Clinical Biochemistry, University of Cambridge,

Cambridge, U.K.
Ingrid Dahlman Karolinska Institutet, Department of Medicine, Karolinska
University Hospital-Huddinge, Stockholm, Sweden
Jasmin Divers Section on Statistical Genetics, Department of Biostatistics, University
of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
Vernon Dolinsky Department of Molecular and Integrative Physiology, University of
Michigan Medical Center, Ann Arbor, Michigan, U.S.A.
Hélène Dollfus Laboratoire EA 3949, Faculté de Médecine de Strasbourg, Centre
de Référence pour les Affections Genetiques Ophtalmologiques, Hôpitaux
Universitaires de Strasbourg, Strasbourg, France
Cédric Dray INSERM, U858, Institut de Médecine Moléculaire de Rangueil and
Institut Louis Bugnard, Université Paul Sabatier, Toulouse, France
Oenone Dudley Institut de Biologie du Développement de Marseille Luminy,
Marseille, France
Sven Enerbäck Medical Genetics, Department of Medical Biochemistry, Göteborg
University, Göteborg, Sweden
I. Sadaf Farooqi Departments of Medicine and Clinical Biochemistry, Addenbrooke's
Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, U.K.
C. Gallou-Kabani INSERM, AP-HP, Université Paris Descartes and Faculté de
Médecine, INSERM Unit 781, Clinique Maurice Lamy, Hôpital Necker-Enfants
Malades, Paris, France
M.S. Gross INSERM, AP-HP, Université Paris Descartes and Faculté de Médecine,
INSERM Unit 781, Clinique Maurice Lamy, Hôpital Necker-Enfants Malades, Paris,
France
Jorg Hager IntegraGen SA, Evry, France
Jennifer R. Harris Department of Genes and Environment, Division of
Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
Johannes Hebebrand Department of Child and Adolescent Psychiatry, University of
Duisburg-Essen, Essen, Germany
Anke Hinney Department of Child and Adolescent Psychiatry, University of
Duisburg-Essen, Essen, Germany
Jens Juul Holst Faculty of Health Sciences, Institute of Biomedicine, The Panum
Institute, University of Copenhagen, Copenhagen, Denmark
C. Junien INSERM, AP-HP, Université Paris Descartes and Faculté de Médecine,
INSERM Unit 781, Clinique Maurice Lamy, Hôpital Necker-Enfants Malades, Paris,
France
Sona Kang Department of Molecular and Integrative Physiology, University of
Michigan Medical Center, Ann Arbor, Michigan, U.S.A.
Jaakko Kaprio Department of Public Health, University of Helsinki and Department
of Mental Health and Alcohol Research, National Public Health Institute, Helsinki,
Finland
Nicholas Katsanis McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins
University, Baltimore, Maryland, U.S.A.
Contributors xiii

Irina Kratchmarova Center for Experimental Bioinformatics, Department of

Biochemistry and Molecular Biology, University of Southern Denmark, Odense,
Denmark
Karsten Kristiansen Eukaryotic Gene Expression and Differentiation Group,
Department of Biochemistry and Molecular Biology, University of Southern Denmark,
Odense, Denmark
Martin Kussmann Functional Genomics Group, Bioanalytical Science Department,
Nestlé Research Center, Lausanne, Switzerland
Dominique Langin INSERM, U858, Laboratoire de Recherches sur les Obésités,
Institut de Médecine Moléculaire de Rangueil, Institut Louis Bugnard IFR 31,
Université Paul Sabatier, and Centre Hospitalier, Universitaire de Toulouse,
Toulouse, France
Philip Just Larsen Rheoscience, Rødovre, Denmark
Martine Laville Human Nutrition Research Center, Rhône-Alpes, University Lyon-I
and Department of Endocrinology-Nutrition, E. Herriot Hospital, Lyon, France
Rudolph L. Leibel Division of Molecular Genetics and The Naomi Berrie Diabetes
Center, Columbia University Medical College, New York, New York, U.S.A.
Ruth J.F. Loos Medical Research Council (MRC) Epidemiology Unit, Cambridge, U.K.
Cécile Lubrano-Berthelier INSERM, U872, Nutriomique, Centre de Recherche des
Cordeliers, Université Pierre et Marie Curie-Paris6, Paris, France
Ormond A. MacDougald Department of Molecular and Integrative Physiology,
University of Michigan Medical Center, Ann Arbor, Michigan, U.S.A.
Lise Madsen Eukaryotic Gene Expression and Differentiation Group, Department of
Biochemistry and Molecular Biology, University of Southern Denmark, Odense,
Denmark
Patrik K.E. Magnusson Department of Medical Epidemiology and Biostatistics,
Karolinska Institute, Stockholm, Sweden
Ariane Minet Eukaryotic Gene Expression and Differentiation Group, Department of
Biochemistry and Molecular Biology, University of Southern Denmark, Odense,
Denmark
Béatrice Morio INRA, UMR 1019, Unité de Nutrition Humaine, Clermont-Ferrand,
France
Solomon Musani Section on Statistical Genetics, Department of Biostatistics,
University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
Françoise Muscatelli Institut de Biologie du Développement de Marseille Luminy,
Marseille, France
David Mutch INSERM, U872, Nutriomique, Centre de Recherche des Cordeliers,
Université Pierre et Marie Curie-Paris6, Paris, France
Jean-Michel Oppert Department of Nutrition, Pitié-Salpétrière Hospital, AP-HP,
Université Pierre et Marie Curie-Paris6, and Human Nutrition Research Center
Ile-de-France, Paris, France
Stephen O'Rahilly Departments of Medicine and Clinical Biochemistry,
Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust,
Cambridge, U.K.
Matej Oresic VTT Technical Research Centre of Finland, Espoo, Finland
xiv Contributors

Miguel Padilla Section on Statistical Genetics, Department of Biostatistics, University

of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
Rasmus Koefoed Petersen, Eukaryotic Gene Expression and Differentiation Group,
Department of Biochemistry and Molecular Biology, University of Southern Denmark,
Odense, Denmark
Daniel Pomp Departments of Nutrition and Cell and Molecular Physiology,
The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Tuomo Rankinen Human Genomics Laboratory, Pennington Biomedical Research
Center, Baton Rouge, Louisiana, U.S.A.
Finn Rasmussen Child and Adolescent Public Health Epidemiology Group,
Department of Public Health Sciences, Karolinska Institute, Stockholm, Sweden
Frédéric Raymond Functional Genomics Group, Bioanalytical Science Department,
Nestlé Research Center, Lausanne, Switzerland
David T. Redden Section on Statistical Genetics, Department of Biostatistics,
University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
Treva Rice Division of Biostatistics and Department of Psychiatry, Washington
University in St. Louis School of Medicine, St. Louis, Missouri, U.S.A.
Elke Roschman IntegraGen SA, Evry, France
Roland Rosmond Partille, Sweden
Alessandro Serretti Institute of Psychiatry, University of Bologna, Bologna, Italy
Thorkild I.A. Sørensen Institute of Preventive Medicine, Copenhagen University
Hospitals, Centre for Health and Society, Copenhagen, Denmark
Gregory M. Sutton Pennington Biomedical Research Center, Louisiana State
University System, Baton Rouge, Louisiana, U.S.A.
Antonio Tataranni Sanofi-Aventis, Bridgewater, New Jersey, U.S.A.
Hemant K. Tiwari Section on Statistical Genetics, Department of Biostatistics,
University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
James L. Trevaskis Pennington Biomedical Research Center, Louisiana State
University System, Baton Rouge, Louisiana, U.S.A.
Christian Vaisse Diabetes Center and Department of Medicine, University of
California, San Francisco, San Francisco, California, U.S.A.
Philippe Valet INSERM, U858, Institut de Médecine Moléculaire de Rangueil and
Institut Louis Bugnard, Université Paul Sabatier, Toulouse, France
Laura K. Vaughan Section on Statistical Genetics, Department of Biostatistics,
University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
Hubert Vidal INSERM UMR870, INRA U-1235, and Human Nutrition Research
Centre, Laennec Medical Faculty, Lyon 1 University, Lyon, France
Antonio Vidal-Puig Department of Clinical Biochemistry, University of Cambridge,
Cambridge, U.K.
A.Vigé INSERM, AP-HP, Université Paris Descartes and Faculté de Médecine,
INSERM Unit 781, Clinique Maurice Lamy, Hôpital Necker-Enfants Malades, Paris,
France
Karani S. Vimaleswaran Medical Research Council (MRC) Epidemiology Unit,
Cambridge, U.K.
Contributors xv

Stéphane Walrand INRA, UMR 1019, Unité de Nutrition Humaine,

Clermont-Ferrand, France
Nicholas J. Wareham Medical Research Council (MRC) Epidemiology Unit,
Cambridge, U.K.
Allison W. Xu Diabetes Center and Department of Anatomy, University of
California, San Francisco, San Francisco, California, U.S.A.
 Introduction

According to the World Health Organization, there are an estimated one billion
overweight adults (BMI ≥ 25 kg/m2); 300 million of these are considered clinically
obese (BMI ≥ 30 kg/m2), and the number is steadily increasing. Such staggering
statistics clearly suggest that despite overt recognition of the taxing effects of
obesity on both individual health and well-being and medical and social pro-
grams, we are still succumbing to this global epidemic, and it shows no sign of
abating. Developing countries also face a transition in the alarming progression of
obesity and its related comorbidities, especially diabetes, which has inspired a
combination of the two words in the “diabesity.” All the ancient authors, includ-
ing one of the most ancient, Hippocrates, having an observant clinical eye,
recognized that health risks were more common among obese subjects than lean
ones. In 1956, Jean Vague pointed out the extraordinary variation in obese
phenotypes, and, notably, that fat accumulation on the trunk and especially in the
abdominal part of the body compared to the peripheral deposition, might be
associated with this increased disease risk.
This overwhelming public health problem needs to be addressed in several
ways. In spite of the parallel development of the obesity epidemic and the presumed
obesogenic features of societies, it is clear that, in order to be able to find new ways
of combating the epidemic, we need a better understanding of molecular mechan-
isms that lead to the accumulation of fat. While technological progress over the last
twenty years has yielded the tools to comprehensively explore the perturbed
biochemistry underlying the obese state, it is clear that both the individual’s genetic
makeup and the environment he or she is exposed to are critical for the regulation of
adipose mass function. But discovering whether and how specific genes and specific
environmental factors interact is still a great research challenge in this field. Finding
the most efficient way of interfering with this process will obviously require much
more progress in the identification of the diverse environmental factors that may
interact with a given biological susceptibility to favor fat mass accumulation in
different areas of the body. Medical and nutritional recommendations based on
genetically undefined and/or environmentally heterogeneous population-based
studies have had minimal success. Tremendous efforts have been invested in
identifying new drug targets, so far with limited success, but the search is ongoing.
It is this relative lack of success that is now paving the way for the widely
discussed concepts of personalized medicine and nutrition, which take into account
genetic, environmental, and biological complexity at the population level. It is
hoped that an important component of this complexity is the admixture of many
different elements that, when disentangled, may lead to more straightforward and
specific interventions that can be successfully administered at the individual level.
However, before realizing either of these ambitious ideas, the genetic compo-
nents underlying obesity must be elucidated.
The idea that genetic susceptibility may contribute to the development of
overweight and obesity is not new. In an 1872 medical treatise, Hufeland, a

xvii
xviii Introduction

German physician, in his definition of obesity noted, “In general, a congenital

disposition has a big influence; so some people remain skinny in spite of the
richest food, and others become obese whereas they are submitted to restriction.”
Even if this statement was a bit of a caricature, more than one century later,
experiments with humans aimed at modifying an individual’s environment
revealed extraordinary individual variations in weight gain or weight loss in
response to changes in food intake and/or physical activity.
At the beginning of the 20th century, works by Davenport (1923) mention
that obesity tends to run in families. The development of genetic epidemiology
using accurate statistical tools for data analysis of large populations of families,
especially families with adopted children and twins, showed that various mea-
sures of obesity or fatness, such as body mass index, are influenced by genes
throughout the range. On the other hand, the environmental influences are as
obvious and clearly proven. The rapidly developing obesity epidemic in almost all
world populations not subject to famine, is in itself a clear demonstration of the
role of the environment, although it remains to be unraveled which environmental
factors are crucial.
In spite of the diversity of environmental conditions, the familial correlation
appears to be present everywhere, and twin and adoption studies indicate that
among adults living separately, the familial correlation is due to the genetic
relationships. While family members live in the same household, there is some
contribution from the shared environment, especially in the children, but this
fades away when the family member leaves the home. How heritable the different
obesity traits are is less clear at this stage, but it is necessary to distinguish
between the various obesity phenotypes in future research of both the genetic and
environmental influences. The genetic epidemiology shows that the common
forms of obesity must be multifactorial conditions influenced by many genes and
many different environmental factors, and this has set the stage for the ongoing
and future research that tries to elucidate the origins of obesity in general and the
epidemic in particular.
In the past ten to fifteen years, the study of complex diseases has benefited
greatly from the extraordinary advances made in molecular biology. While each
form of obvious familial obesity was first thought to be a disease obeying
Mendelian traits of inheritance for single major genes, the application of new
technologies has painted a far more complex picture and led to unsuspected and
fascinating new developments.
An illustrative example is provided by such syndromic forms of obesity as
the Bardet-Biedl or Prader-Willi syndromes, among others. Although very rare,
these cases have been well defined in the clinical context for years. Analysis of the
genetic components of these conditions now suggests that multiple genes within a
biological pathway may produce identical or close phenotypes. New fields of
research have been opened by the molecular investigation of the Bardet-Biedl
syndrome, for example, into the potential and mysterious role of ciliary cells in
controlling some mechanisms of body-weight regulation. This means that pursuing
the molecular exploration of rare but well-defined human phenotypes or syn-
dromes is valuable for opening up fascinating new tracks, although the relevance
for common obesity is still to be elucidated. Obesity stemming from a single,
naturally occurring, dysfunctional gene (i.e., monogenic obesity) is both severe and
rare when compared to the more common form of obesity, in which numerous
genes make minor contributions to the phenotype (i.e., polygenic obesity).
Introduction xix

Although some genetic candidates underlying monogenic obesities in the

mouse have been defined, transferring this knowledge to man has produced more
questions than answers. Indeed, the molecular approach has revealed novel
candidate genes for the various “types” of human obesities, but it has also
suggested that several cases previously defined as monogenic are genetically more
complex than previously thought. This has made gene-gene and gene-environment
interactions fundamentally important processes for the understanding of the
mechanisms involved in fat mass expansion.
In view of these interactions, it is a great challenge to provide foolproof
guidelines for the identification of a novel candidate gene that is important
in determining a complex trait. Features such as expected-effect size, context-
dependency, multiple testing, sample size, and replication must continue to be
addressed on an experiment-by-experiment basis. Progress in the knowledge
of the human genome, development of comprehensive technologies, and, notably,
new analytical strategies will permit both the genetic and environmental aspects
of complex traits to be addressed simultaneously.
The task is so great that success will ultimately lie with the creation of
international consortia working toward a common goal, bringing together the
expertise and resources needed to define and functionally annotate the genetic
factors underlying the various forms of obesity. Our ability to identify promising
candidates is progressing rapidly in the postgenomic era. This era is characterized
by immense progress in the development of the tools of molecular biology (e.g.,
microarrays, mass spectrometry, bioinformatics, and so forth). Whether the con-
sortia aim to sequence genomes, develop classification terminologies, create pub-
licly accessible databases (such as HapMap), or provide scientific and ethical
guidelines for emerging fields, the effect of collaboration is the same: Pooling
together resources and knowledge from laboratories around the world achieves
ambitious goals far more quickly and accurately than can be done by an indivi-
dual research group working alone.
Programs comprising academic and industrial partners aim to study gene-
environment interactions and identify the genomic processes susceptible to envir-
onmental stimuli. Within such programs the use of comprehensive platforms (i.e.,
genetics, transcriptomics, proteomics, peptidomics, lipidomics, and metabolomics)
coupled with clinical data will probably play an important role in elucidating the
perturbed functions leading to obesity.
In this rapidly changing context, we should not underestimate the necessity
of adequately defining the human obesity phenotype, which is characterized by
great diversity in subphenotypes and by natural evolution within the individual
passing through different stages, which are probably associated with different
molecular mechanisms. Bioclinical resources and individual characterizations
created in accordance with this complexity are warranted. In this context, modern
tools of exploration precisely aimed at dissecting the individual’s obesity subphe-
notypes in population-based studies are needed. Indeed, individual complexity in
humans relates to the influence of common disease alleles in different genetic
backgrounds. Various genetic combinations, possibly influenced by different
epigenetic factors—including the role of in utero environmental determinants—or
environmental factors during an individual’s lifetime are what face us in the task
of deepening our understanding of the origin of obesity. Evaluation of perturbed
functions at the multi-tissue level (for example, innovative imaging coupled with
metabolic investigation) and environmental profiles are needed. Until now, the
implacable feuds of aspirants to the disrupted empire of the
Almohades. The impracticability of again uniting the discordant
constituents of that empire was not understood, or even considered.
The rival contestants sacrificed every consideration of patriotic and
religious duty to the gratification of their revenge or the furtherance
of their ambition. Their subjects beheld with apprehension and
disgust the purchase of Christian aid against their brethren by the
payment of extravagant subsidies and the surrender of the bulwarks
of the frontier. They saw the resources wasted which, if properly
employed, might have redeemed from infidel occupation vast tracts
of territory whose fertility had once been the pride of the industrious
people of Andalusia. They saw their own arms turned upon their
neighbors, when the combined efforts of both would have sufficed, if
not to successfully resist, at least to check the progress of the
common foe. Three princes indiscriminately arrayed against each
other occupied an unenviable prominence in this suicidal conflict. In
the West, Yahya, the former Almohade sovereign, held Seville. In the
East, his nephew Mohammed-al-Ahmar and the celebrated partisan
Mohammed-Ibn-Hud contended for the possession of the provinces
of Murcia and Granada. The latter, in the ignoble desire to satiate his
vengeance, had secured from the Castilians temporary immunity
from molestation by the daily payment of a thousand pieces of gold.
This ignominious contract was at length rescinded on account of the
remonstrances and threats of the Andalusians, whose fields were
ravaged in security by Christian marauders, while Moslem partisans
were cutting each others’ throats under the walls of Murcia. Ibn-Hud,
after a campaign which terminated with little glory and still less honor
for either party, succeeded in compelling the Christians to retreat,—a
step which they anticipated by the slaughter of their captives.
Repeated raids into the southern provinces were gradually but surely
preparing the way for Christian supremacy. Relying upon the
additional prestige acquired by his recent advantage over the
Castilians, Ibn-Hud negotiated a treaty with Ferdinand, which
stipulated for a cessation of hostilities for four years. The results of
this negotiation indicate the slight regard for the most sacred
agreements entertained by a prince whose services to the Church
have procured for him the questionable honor of canonization. No
engagement could have been assumed under more solemn
circumstances. The treaty was ratified by the signatures, by the
oaths, by the pledges of regularly authorized representatives of the
contracting parties. An enormous sum of gold was paid by the
Moslem as a preliminary consideration. But priestly casuistry and
royal ambition had little respect in times of universal ignorance for
the maintenance of national honor or the observance of public faith.
The prelates whispered in the ear of the King that it was an
established principle of the ecclesiastical polity that no contract was
binding which was entered into with an enemy of Christ. The
suggestion was in thorough accordance with the views of Ferdinand,
accustomed, moreover, to implicit obedience to the directions of his
spiritual counsellors. A rare and tempting opportunity was offered to
violate the agreement entered into with the Saracens, for which the
price had already been received. The attention of the latter—who
fancied themselves secure from foreign hostility—had been diverted
from their hereditary foe, and was now concentrated on each other.
Civil war was raging on the borders of Granada, where Mohammed-
Ibn-Hud and Mohammed-al-Ahmar were engaged in a desperate
struggle for the possession of Eastern Andalusia. In consequence of
this, as well as of the presumed inviolability of the treaty, the entire
valley of the Guadalquivir had been stripped of troops. The open
country was practically defenceless. The garrisons of the great cities
were insufficient to resist a siege. Exhausted by a long series of
inroads, the peasants were beginning to again cultivate their farms
and rebuild their desolate homes. No one suspected that the storm
was about to break forth more furiously than ever. Repeated
examples of Christian perfidiousness had been insufficient to teach
the Moslems to what depths ecclesiastical infamy, in the prosecution
of schemes of worldly advantage, was ready to descend.
Some Moorish prisoners, whom the commander of a small
detachment of freebooters was about to send to execution as the
most convenient way of disposing of them, promised, in return for
their lives, to place the eastern suburb of Cordova, which virtually
commanded the city, in the hands of the Christians. The proposal
was too alluring to be declined; the risk of failure was not considered;
and, in an age characterized by the most foolhardy and romantic
exploits, the greater the danger the more fascinating it appeared to
the audacious spirits who lived upon the excitements of border
warfare. During a stormy night in the month of January, 1236, the
assailing party, numbering but a few hundred, advanced in silence to
scale the walls of one of the largest Moslem cities of the. Peninsula,
which, although greatly diminished in population since the era of the
khalifate, still contained more than a hundred thousand inhabitants.
A few agile soldiers succeeded in reaching the ramparts; the guard
was surprised and despatched, and the gate was at once thrown
open to their comrades. The suburb thus entered by the Christians
was one of the five principal quarters or wards into which the
metropolis of Moorish Spain had been originally divided. Completely
isolated from the remainder of the capital by a line of fortifications, it
gave an enemy far greater facilities for defence than the mere
penetration into a walled town of ordinary character would have
afforded. The first intimation of their misfortune was communicated
to the citizens at daybreak by the tumult which accompanied the
inauguration of pillage and murder. Taken completely by surprise and
hemmed in on every side, there was no possibility of effectual
resistance and but little hope of escape. The garrison issued from
the citadel, but were unable to dislodge the Christians, who, inured
by long practice to similar encounters, and favored by the tortuous
streets and by the towers occupied by the cross-bowmen, easily held
their ground against overwhelming odds. But notwithstanding their
temporary success, their situation was desperate. It was hardly
possible that so small a force would be able to maintain itself in the
centre of a hostile community until reinforcements could arrive. Yet
such was the undaunted resolve of the assailants, who, now
besieged in turn, were subjected to the harassing effects of
unremitting conflict. Messengers requesting aid had been early sent
to Alvar Perez, the commandant of the frontier, and to King
Ferdinand at Leon. The knights of Calatrava and Alcantara
responded with eagerness to the call to arms, and with these and a
considerable body of militia, to whom were confided the patrol and
defence of the border, the Castilian general hastened to Cordova.
When he received the message, Ferdinand was at a banquet. His
martial followers learned with exultation of the prospect of a new
campaign, and the scene of mirth and festivity was at once
exchanged for the stern and serious preparations for war. The
season was most unpropitious to military operations. The winter
rains had flooded the country, raised the streams far beyond their
banks, and rendered the roads impassable. A long and toilsome
journey separated the capitals of Leon and Andalusia. But nothing
could daunt the spirit of the Castilian and Leonese chivalry, whose
religious fervor and martial enthusiasm were augmented and
stimulated by the example of their king. The exigencies of the
situation would not tolerate delay. Communication with remote
districts was difficult, and but three hundred horsemen could be
raised to follow Ferdinand in an expedition which promised far more
danger than glory. The Christians surrounded at Cordova formed but
an insignificant force, wholly inadequate, it would at first appear, to
the conquest of a strong and populous capital. But fortune, which
had so frequently aided in promoting the designs of Spanish
audacity, again interposed in favor of the champions of the Cross. In
their extremity, the Cordovans had repeatedly implored Mohammed-
Ibn-Hud, whose army was encamped at Ecija, to raise the siege
before more Castilian troops arrived. Had these requests been
heeded, the utter destruction of the Castilians could hardly have
been prevented. That cautious leader, however, entertained a
wholesome dread of the prowess of his enemies, and hesitated to
confront in battle, even when the conditions were all in his favor, the
redoubtable warriors of the North. He delayed, he temporized, he
sent renegade spies into the Christian camp, who, having been
detected, seized the opportunity to stipulate for pardon on condition
of their return of false reports to the Moorish general. Their
representations of the exaggerated numbers of and hourly
increasing accessions to the Castilian army were believed; Ibn-Hud
declined to risk his power upon the event of a single engagement,
and the Cordovans beheld with sorrow and indignation the
disappearance of their only hope of escape. Retribution soon
overtook the vacillating and too credulous Moslem prince. The siege
of Valencia had been formed by the King of Aragon, and the
entreaties of its Emir had more weight with Ibn-Hud than the plaintive
appeals of his other imperilled countrymen. While on his march to
reinforce that monarch he halted at Almeria. That city was governed
by a secret partisan of Mohammed-al-Ahmar, who saw in this
unexpected visit a convenient opportunity to increase his favor with
his patron. A magnificent banquet was prepared, and the noble and
wealthy merchants of Almeria contended with each other in honoring
the distinguished guest. The choicest wines of Spain were provided
in the greatest variety and profusion for the canonically prohibited,
but none the less acceptable, entertainment of the assembled
Moslems. At a late hour Ibn-Hud was conducted to his chamber and
drowned in the basin of a fountain by slaves who had received their
instructions from the governor himself. His death was officially
attributed to apoplexy resulting from intoxication; but popular
suspicion was not slow in tracing to its true origin the sudden end of
the victim of broken faith and perfidious hospitality.
By the assassination of Mohammed-Ibn-Hud was removed the
greatest remaining obstacle to Castilian conquest. He alone, of all
the Moorish potentates of Spain, had refused to barter Moslem
territory for Christian aid. When his political necessities required the
co-operation of the infidel power, that power was reluctantly
purchased with gold, and not with the surrender of fortresses to be
used as a basis for hostile operations, and which could never be
regained. He was the most prominent representative of Hispano-
Arab nationality that had appeared for generations in the Peninsula.
In opposition to him were arrayed the various elements which, in
many respects mutually inimical, combined either purposely or
unconsciously for the subversion of the Saracen empire, the greed
and brutality of the Berbers, the fanaticism of the theologians, the
hopeless aspirations of a horde of princely adventurers, the
indomitable energy and perseverance of the Christian sovereigns.
Against these destructive agencies Ibn-Hud conducted a brave but
hopeless struggle. Prejudice against African domination had been
aggravated by centuries of crime and oppression. But Berber
influence was still potent in many communities, and in some
predominantly so. Immigration and intermarriage had contributed
largely to consolidate and preserve the power originally obtained by
violence. Ibn-Hud was in no sense the champion of the clergy. He
was accused of atheism; his speech was often blasphemous, and he
was habitually addicted to immoderate indulgence in wine. But these
faults would have been readily condoned by ecclesiastical
indulgence if their possessor had exhibited an edifying subserviency
to the ministers of religion. Instead of this, however, he lost no
opportunity of turning the hypocritical professions of the faquis into
ridicule, a course which, by alienating a numerous and influential
sect, materially accelerated the hour of Christian triumph. The
suicidal behavior of the petty rulers and soldiers of fortune who
indulged the fallacious hope of empire has already been repeatedly
alluded to in this work. United, they might have deferred for a time
the inevitable day of reckoning for official misconduct and national
corruption; separated and hostile, they destroyed the basis of all
power and social organization, and the stability of none so quickly as
their own.
The murder of Ibn-Hud caused the immediate disbanding of his
troops, and the investment of Cordova proceeded without fear of
interference from an army which, properly commanded, could easily
have raised the siege. Ali-Ibn-Yusuf, the brother of the dead prince,
obtained the Emirate of Murcia, of which, however, he was soon
deprived by assassination through the instrumentality of
Mohammed-al-Ahmar, and, together with the principality of Almeria,
it was added to the territory of the rising kingdom of Granada.
Their desertion by Ibn-Hud and the intelligence of his tragic death
struck the citizens of Cordova with terror. Notwithstanding his
pusillanimous conduct, they had still hoped that he might ultimately
effect their deliverance. Now, however, there was no one to whom
they could turn for succor. News of the important enterprise in which
the King of Castile and Leon was engaged had already spread to the
most distant settlements of the Christian territory. Citizen and
peasant, noble and mountaineer, braving the inclemency of an
unfavorable season and the dangers of swollen torrents and flooded
highways, hastened to the seat of war. The dismay of the besieged
increased with each shout which announced the arrival of a new
detachment at the Castilian camp. The Christians made frequent and
desperate attempts to carry the place by storm. The garrison was
worn out with the fatigue it was compelled to undergo; and the
effeminate and disorderly populace were ill-qualified to perform the
duties of soldiers. Walls and towers were tottering under the blows of
the military engines. The suddenness of the attack had found the
city, which, nominally protected by a truce, dreamed of nothing less
than a siege, entirely unprovided with supplies. Food became
scarce. It was manifest that the inevitable destiny of the ancient
metropolis of the Ommeyade khalifate could not long be postponed.
Actuated by motives of self-preservation and humanity, the Moorish
authorities determined to make terms with the King, and to avoid if
possible the awful calamities which had been visited upon so many
of the unfortunate cities of Andalusia. The capitulation was made
under the distressing conditions usually imposed in such cases upon
the vanquished. The inhabitants were required to abandon
everything and to depart from the province. As the long and weeping
train of penniless exiles passed out of the gates on one side the
conquerors entered on the other. It was with the greatest display of
military and ecclesiastical pomp that the Christians took possession
of the famous Moslem capital. The old walls echoed the tread of
mailed squadrons, the stirring notes of the trumpet, and the solemn
chants of the clergy, who, in all the splendor of glittering vestments,
jewelled censer, and crucifix, occupied the post of honor in the
procession. The royal standard of Castile and Leon was planted on
the highest tower of the fortifications. It was with wonder, not
altogether unmingled with reverence, that the ignorant and ruffian
soldiery viewed the exquisite beauty of the Great Mosque,—the
shrine which, venerated as a sanctuary, had invited the pilgrimage of
the devout of distant nations; the temple which had been enriched by
the emulous munificence of the most opulent and polished princes of
Europe; the edifice which, alone of all the marvellous architectural
creations of the Hispano-Arab age of gold, had survived intact the
fury of religious discord, the tumult of revolution, the extinction of
dynasties, the destruction of empires. Amidst the vicissitudes of
invasion, conquest, and revolt, a veneration akin to idolatry had
always invested the Djalma of Abd-al-Rahman. The exterior still
glowed with the warm and brilliant coloring of the Orient. The court-
yard still exhibited in its diversified horticulture the capricious taste of
the Andalusian gardener. Inside, the presence of the myriads of
pious worshippers who had trodden its interminable aisles in the
course of five eventful centuries had left few permanent traces. The
pattern of the elegant pavement was partially effaced. Within the
Mihrab—the centre of the little sanctuary which looked towards the
temple of Mecca—a channel deeply worn in the marble floor
indicated where countless pilgrims, in imitation of the ceremonies of
the Kaaba, had seven times made its circuit on their knees. These,
however, were the sole but eloquent testimonials of the continuous
devotion of fifteen generations. The walls were hung with that richly
embossed and decorated leather whose name indicated the
Ommeyade capital as the place of its invention and manufacture.
The ceiling sparkled in the semi-obscurity with its gilded pendentives
and silver stars. Upon the arches of the Mihrab appeared in
untarnished beauty the dazzling mosaics which had been the pride
of the Byzantine artisan. The treasures of the mosque, the mimbar,
or pulpit, the chandeliers, lamps, and censers, were all, save one, in
their accustomed places. The most precious object of Moslem
reverence, the Koran of Othman, regarded as the talisman of Spain,
had been carried away to Africa by the Almohade monarch, Abd-al-
Mumen, and with its departure, according to the superstitious belief
of the devout, had vanished the last warrant of the security of
Moslem power. That ornament of the Mihrab—the relic stained with
the blood of a martyred khalif, the first of a race whose martial
energy and literary endowments were destined to dignify and honor
the royalty of Islam—was now in the hands of foreign and
inappreciative barbarians. From the ceiling were suspended the bells
of the church of Santiago, placed there by the great Al-Mansur,
significant trophies of the victorious career of that most renowned of
Moorish commanders. But once before in its history had this
splendid temple, which, in public estimation, was inferior in holiness
only to the mosques of Mecca and Jerusalem, been desecrated by
the presence of the infidel. Now, however, it was eternally lost to the
religion for the celebration of whose rites it had been founded. The
Mussulman pilgrim, attracted by the reputation of its sanctity and the
fame of its unrivalled magnificence, could henceforth no more invoke
the name of the Prophet within its venerable walls.
 The vast edifice was almost deserted as the Christian procession,
headed by the greatest prelates of Spain, filed slowly through its
portals. A few of the attendants peered curiously from behind the
pillars at the splendid array, whose appearance was the ominous
signal of the final suppression of the Mohammedan faith in the
Peninsula. Amidst the prayers of the priests and the shouts of the
soldiery, the cross was raised upon the cupola of the Mihrab. In
accordance with the prescribed ceremonies of the Roman Catholic
ritual, the edifice was cleansed of the abominations presumed to
have infected it under the ministrations of another and a hostile
belief. The mosque was dedicated as a cathedral, whose see was
enriched with donations of some of the most valuable estates of the
conquered territory. In pious retribution for the sacrilege which had
appropriated them, the bells of Santiago were returned to the church
from which they had been taken upon the shoulders of Moorish
captives. The latter, as they painfully traversed the extensive regions
that separated the plains of Andalusia from the cheerless Galician
solitudes—regions which once trembled at the very mention of
Moslem heroes—might well reflect upon the transitory character of
religious faith and the instability of human greatness.
The compulsory evacuation of Cordova struck a blow at its
prosperity from which it never recovered. With natural advantages
enjoyed by few communities, it remains to this day the most poverty-
stricken and stagnant of the great cities of Spain. Its vitality is
preserved by the wealth and resources of its ecclesiastical
establishment alone. Its markets are deserted, its thoroughfares
grass-grown and silent. A grotesque and tawdry church rises in the
very centre of the mosque of Abd-al-Rahman, impairing its
symmetry, and furnishing an eternal monument to the folly and
prejudices of a fanatical priesthood. The banished population carried
with it a thrift and an industry which centuries have not been able to
replace. Many arts, brought to a high degree of perfection,
disappeared with its expulsion. The walls begun by the Cæsars, and
greatly extended by the princes of the House of Ommeyah,
embraced within their circumference the original area of the once
populous Moslem capital. Time, however, had dealt severely with
that far-famed city. Entire quarters had been depopulated by the fury
of rebellion, the vicissitudes of political fortune, the ravages of
conquest. Streets, formerly crowded with merchants and brokers of
every clime, were impassable from the accumulated rubbish of
demolished houses. The alcazar, which adjoined the mosque, was a
dismantled ruin. The rage of the populace and the vandalism of
African invaders had swept away the palaces whose number and
elegance had awakened the admiration of every beholder. The villas
of the suburbs had disappeared. The lovely gardens, in whose
culture and preservation had been exhibited the utmost perfection of
horticultural art, were now impenetrable thickets, from whose tangled
depths, here and there, rose a heap of fallen columns or a broken
horseshoe arch. Under the khalifate, the Valley of the Guadalquivir
was so thickly settled as to present the appearance of one vast
community, and from Cordova to Andujar countless villages attested
the fertility of the soil and the thoroughness of its cultivation. At the
time of the Christian occupation this region had become a desert,
and a desert it has since remained. For the intelligence and energy
of the Moslem were substituted the sloth and ignorance of the monk;
ecclesiastical councils, in which were solemnly discussed the alleged
inspired origin of absurd dogmas, usurped the place of the literary
assemblies of the khalifs; and the monastery and the episcopal
palace, with their secret crimes and open vices, rose upon the ruins
of institutions of learning whose instruction had developed the
greatest minds of Europe, and whose influence and principles had
dignified even the papal throne.
While the Castilians were prosecuting their important campaign in
the West, the genius of the King of Aragon was again asserting itself
in the principality of Valencia. Under the lax system of political
morality prevalent during the Middle Ages, an insignificant event was
not infrequently made the pretext for a protracted and bloody war.
Abu-Djomail, Emir of Valencia, for some reason deferred the delivery
of tribute to Jaime, his suzerain, and the latter, elated by the
conquest of Majorca, determined to make this an excuse to add to
his already extensive dominions the most valuable remaining
province of Spain. Profoundly politic as well as brave, the King of
Aragon obtained the official sanction of Pope Gregory IX. for his
meditated design, and the inauguration of a fresh crusade was
proclaimed to the bold adventurers of Europe. An extraordinary tax
was voted for the pious enterprise by the Cortes of Catalonia; a great
army was assembled, and the campaign was begun by the siege of
Burriana, a strongly fortified seaport, whose numerous garrison and
maritime relations with the neighboring states of Africa promised a
long and vigorous resistance. This expectation was verified to the
letter. Several months elapsed before the place surrendered. It was
midwinter, for the impetuosity of Jaime did not consider, in the attack
on an enemy, either the disadvantages of the season or inferiority in
numbers. In the conduct of this siege he displayed the qualities of an
able commander even more conspicuously than he had done before
Majorca. He personally directed the operations of the military
engines. He led the troops to the breach. He exercised careful
supervision over the camp, provided for the comfort of the soldiers,
dressed the wounds of the injured, cheered with words of
consolation the last moments of the dying. The severe privations it
was called upon to endure damped the enthusiasm of the army.
Some of the discontented nobility demanded that the siege be
raised. The King refused, even in the face of the imminent desertion
of a majority of his troops. While the malcontents remained sullenly
in camp, he, supported only by a few faithful followers, skirmished
daily with the enemy, who, having learned the condition of affairs,
had assumed the offensive. At length the determination of the King
prevailed, and the nobles returned to their duty. The siege was
thenceforth pressed with redoubled energy, and Burriana was soon
added to the long list of Jaime’s conquests. Its reduction caused the
immediate surrender of the strong city of Peniscola and of a
considerable number of towns in the Valencian territory. The
disaffection of the Aragonese and Catalonian nobility was removed
by these successes, and their fidelity was confirmed by the
immediate investiture of the most distinguished of their number with
the larger part of the conquered domain,—a politic measure which
increased their military and feudal obligations, while it temporarily
secured their attachment and gratitude.
From the day of his accession to the hour when he entered the
Moorish capital in triumph, the absorbing desire of Jaime was the
conquest of Valencia. The difficulties which presented themselves to
the realization of this project only confirmed the resolution of the
King. A few miles from the city stood the fortress of Puig. Its
impregnable situation and close proximity to the metropolis of the
kingdom rendered its possession highly advantageous to an army
besieging Valencia. It had fallen into the hands of the Aragonese
after the capitulation of Peniscola, and its defences had been greatly
strengthened by the Christian engineers. During the absence of
Jaime, an army of forty thousand Moslems, commanded by the Emir
in person, appeared before it. The garrison was greatly inferior in
numbers, but composed of picked warriors never accustomed to
count their enemies excepting after a victory. Their intrepidity hardly
allowed them to await the approach of the Valencians. They issued
from the gates; their sudden and impetuous attack disconcerted their
adversaries; and the discomfiture of a host of twenty times their
number added a new trophy to the innumerable triumphs of Christian
valor. The battle of Puig destroyed the confidence of the Moslems of
Valencia, and they never again ventured to encounter their terrible
antagonists in the open field.
Despite the favorable beginning of the campaign, the Aragonese
army was daily reduced by desertions, and when, a few weeks
afterwards, it encamped before Valencia, it mustered less than
fifteen hundred strong. Rarely had an enterprise of such importance
been undertaken with so small a force. In addition to its numerical
weakness, its efficiency was impaired by a general feeling of
suspicion, engendered by a lack of confidence and an absence of
discipline. Many nobles abandoned their king, often without notice,
taking their retainers with them. Those who remained could not be
relied on, and had, in fact, good reason for discontent. The daily
winter rains increased the difficulty of military movements and the
danger of disease. Few of those who had served in the former
campaign cared for a repetition of the experiences before Majorca.
The presence of a brave and treacherous enemy rendered
increasing vigilance indispensable and magnified the already
arduous labors of a siege whose issue, under existing
circumstances, could hardly be successful. The pay of the soldiers
was in arrears, and the treasure chest, exhausted by unusual
demands and plundered by dishonest custodians, was empty. The
camp resounded with complaints. The murmurs of the courtiers were
not suppressed even in the royal presence. When the King
announced his intention to return for the purpose of seeking
reinforcements, the remaining nobles declared that they would
accompany him and renounce an undertaking which promised
nothing but disaster. But relief was at hand from a quarter whence
substantial encouragement had already been repeatedly obtained in
wars with the Moorish infidel. The crusading spirit, generally
nourished by incentives wholly foreign to the principles of religion,
which, however, always afforded a convenient pretext for the most
flagrant outrages against humanity, was by no means dormant in
Europe. Another crusade was proclaimed by the Holy See. The
passions of rapacious adventurers were inflamed with the hope of
conquest, while the promise of unlimited pardons, indulgences, and
booty attracted to the standard of the Cross a motley concourse of
criminals, outlaws, and fanatics. France and England furnished
almost all of these recruits, who numbered nearly seventy thousand.
With such an army, which was constantly supplied with provisions by
sea, the ultimate result of the campaign seemed no longer doubtful.
To prove to the enemy, as well as to his own followers, his intention
not to abandon his position until the city should be captured, Jaime
made use of every artifice and expedient at his command. The
Christian camp by degrees assumed the appearance and character
of a permanent outpost. The quarters of the soldiery were
constructed of substantial materials. The Queen, attended by the
ladies of the court, arrived and took up her residence in the royal
pavilion. Operations were pressed with increasing diligence. The
Moors, impressed by these ominous evidences of the unalterable
purpose of the besiegers, attempted to negotiate. All the territory
between Teruel, Tortosa, and the Guadalquivir—a region of
boundless fertility and defended by many strong fortresses, together
with a yearly tribute of ten thousand pieces of gold—was offered as
the price of peace. The King, conscious of his advantage, declined to
listen to any terms of accommodation which did not include the
capitulation of the city. The prize almost within his grasp was too
valuable to be made the subject of barter. The traveller who to-day
traverses the province of Valencia is amazed and enchanted with its
productiveness and beauty. Yet what he sees is a comparatively
insignificant portion of that which was once under the highest
cultivation attainable by any system of agriculture. The density of the
population required the greatest economy and labor in the division
and use of both land and water. Hills that are now rocky and barren.
were, under Moorish occupation, covered to the very summits with
verdant terraces. Irrigation, governed by a code of laws which
Spanish conceit and prejudice have never been able to repeal, was
carried to almost absolute perfection. Every product flourished in a
climate not inaptly compared with that of Paradise. The natural
resources and accumulated wealth of such a principality were too
alluring to permit its long continuance in the hands of those whose
skill and patient efforts had founded and perpetuated its prosperity.
At the sight of the voluptuous regions of Southern Spain, the
Christian of the inhospitable North often forgot his country and the
deeds of his heroic ancestors who had wrested with difficulty from
the infidel a foothold in the Pyrenees; in the presence of the lovely
houris of another faith he sometimes renounced his religion and his
God. The Spanish crusades were not characterized by the absurd
but sincere fanaticism which was the chief motive that inspired the
expeditions to Palestine. No kings or courtiers abandoned home,
country, friends, and family to obtain an object of doubtful
expediency in the midst of an arid and scorching desert. No
misguided multitude, roused by ecclesiastical eloquence, undertook
the most interminable of journeys, endured the most horrible of
privations for the recovery of the Holy Sepulchre, which omnipotent
wisdom or Moslem valor had left since the reign of Omar, with a
single slight intermission, in the hands of the infidel. The warriors
who assumed the cross in the Peninsula were men of a widely
different stamp from the followers of Peter the Hermit or the vassals
of Philip Augustus and Richard Plantagenet. It is true that some of
them had served in the Holy Land; but these were not fair
representatives of the brave, the chivalrous, the pious crusaders.
Their incentives had been mercenary, or they may have sought
security for unpardonable crimes in the confused obscurity of a
multitude of strangers. The most ignoble designs were concealed by
the ample but well-worn mantle of religion. The wealth of the Moorish
cities, the seductive influence of the climate when contrasted with
the inclement and dreary atmosphere of Central and Northern
Europe, the beauty and grace of the Mohammedan women were
well known to every nation from Byzantium to Britain. It was no
secret, either, that the population of the terrestrial paradise which
bordered on the Mediterranean had long since lost the prestige and
the strength which had distinguished the armies of the khalifate, and
was not fitted to contend with fierce and powerful warriors reared
amidst cold and privation, trained to martial exercises from infancy,
and whose occupation and pastime alike were war. The
accomplishment of the Reconquest would have been long and
indefinitely deferred had it depended on the exertions of the
Spaniards alone. Credit for the exploits which subdued and
eventually consolidated under the Castilian sceptre the Hispano-
Arab principalities is in no small degree due to the prowess of
adventurers from every country in Christendom. The frenzied
exhortations of monkish zealots were not required to excite the
passions of the foreign crusader who volunteered in the armies of
Jaime and Ferdinand. In his eyes the propagation of the Faith was
merely an excuse for pillage. He was conspicuously negligent in the
performance of his religious duties, extended experience and
observation having thoroughly familiarized him with the
inconsistencies and the failings of the clergy, and inspired him with a
contempt for that order which he was usually at no pains to conceal.
His attachment to the cause of Christ lasted just as long as it was
profitable. Such considerations are not applicable, however, to the
independent Christian population of Spain. With it the extinction of
Moslem domination was a measure of political necessity, of national
existence, of individual freedom. For five hundred years the struggle
had continued. More than once the petty states which had sprung
from the weak and insignificant community established in the
Asturias in the face of Moorish triumph, expanded by ages of
undaunted resolution and superhuman valor, and finally developed
into a number of kingdoms whose mutual antagonisms were the
greatest menace to their stability and power, had been on the point
of submitting once more in humiliating subordination to Moslem
authority, evidenced by the regular and humiliating rendition of
homage. Generations of battle had engendered in the mind of the
Spanish Christian a sentiment of ferocious hatred against the infidel
enemy who had usurped the empire of his ancestors; who had
defeated his most valiant sovereigns; to whose harems had been
consigned the most beautiful maidens of his race, either as a
degrading tribute or as the spoils of war; whose sacrilegious hands
had seized the sacred treasures of his altars; who had deposited
with exultant shouts within the mosque of his capital the bells whose
solemn tones had so often called to their devotions the pilgrims
assembled at the holy shrine of Santiago. The grosser passions of
avarice and military ambition were, indeed, rarely absent from the
motives which prompted the conduct of the mediæval Spaniard.
Inherited prejudice, early education, the maxims of his religious
guides, all had a tendency to intensify the detestation entertained by
him against such as refused assent to the doctrines of his creed. The
Castilian despised the knowledge and the intellectual
accomplishments which made the Moor immeasurably his superior,
but he often reluctantly confessed the bravery of his infidel adversary
in the field. This antipathy and intolerance, while openly encouraged
by the clergy for professional reasons, were in reality less marked
among the ecclesiastics than elsewhere. As their order monopolized
the meagre learning of the time, they were better qualified to
appreciate the scientific acquirements which distinguished the
polished enemies of their faith. As representatives of a system
largely maintained by organized hypocrisy, they condemned in public
what they often studied with wonder and delight in the luxurious
solitude of the convent and the monastery. The prelates as well as
the nobles did not disdain to imitate the vices of the Moslem,
especially condemned by their religion, their canons, the precepts of
their Founder, and the example of the chaste and abstemious
Fathers of the Church. The writings of the heterodox Mussulmans
were not unfamiliar to the more intelligent and inquisitive members of
the Spanish hierarchy. The theological gloom of the episcopal palace
was dispelled by the joyous presence of lovely infidels, whose
caresses were more attractive to the clerical voluptuary than the
monotonous ceremonies of the mass, and whose suggestive
dances, relics of the licentious diversions of Pagan antiquity, were
frequently performed for the delectation of saintly visitors in the most
retired apartments of the ecclesiastical seraglio.
Incentives other than those inspired by disinterested piety had
great weight with the majority of the Spanish clergy. The Church,
through the diligently fostered fears and the misdirected liberality of
its superstitious adherents, was always the greatest beneficiary of a
successful campaign against the Saracen. The lucrative precedent
for the accumulation of treasure, eventually consumed in the
construction and adornment of the palatial religious houses of the
Peninsula, whose number and magnificence, although sadly
diminished, are still sufficient to excite the envy of Catholic Europe,
had already been established. The annual contributions bestowed by
royal munificence or wrung from individual poverty were but a
pittance when compared with the booty to be secured by the Church
militant at the capture of a single Moslem city. Uncanonical
considerations were, moreover, no insignificant inducements to the
martial ecclesiastic to abandon for a time the cope for the cuirass.
The formal and traditional obligations of his order were but lightly
regarded by the Castilian or the Leonese prelate. His vow of poverty
had long been forgotten amidst the boundless epicureanism of
elegant luxury, magnificent furniture, expensive and gaudy raiment,
priceless jewels, the possession of horses whose purity of breed
moved the envy of the greatest nobles, the parade of trains of slaves
whose physical attractions were indisputable proof of the taste and
incontinence of their masters. The Spanish hierarchy, independent of
the Papacy from the early days of Gothic domination, was far from
presenting in its polity the nice distinctions of official rank and the
rigid subordination to superiors exhibited in the profound and
elaborate organization of the papal system. Each prelate enjoyed a
large share of independence in his own diocese, and recent
acknowledgment of the paramount claims of the See of Rome had
not abrogated the ecclesiastical prerogatives confirmed by
prescriptive right based upon the uninterrupted usage of centuries.
The vow of implicit obedience—generally considered an unmeaning
formality and unknown in practice under the Visigoths—was for
generations after the public submission to papal supremacy
disregarded as an imperative obligation of the clergy. Such was the
condition of the Spanish priesthood and such the base and
inconsistent motives which prompted the overthrow of the most
perfect examples of material and intellectual progress which had
adorned and instructed Europe since the climax of Roman
civilization.
The great accession of moral strength secured through the
instrumentality of the Papacy enabled the King of Aragon vigorously
to assume the offensive. A great fortified camp, whose works defied
the feeble and desultory efforts of the besieged, now encircled the
city of Valencia. The machines were placed in position, the walls
were mined, and intercourse with the Moors on the side of the land
effectually intercepted. By the sea, however, communication was as
yet comparatively clear, and pressing messages for assistance were
sent by the beleaguered Moslems to their brethren in Andalusia and
Africa. To these appeals no one responded except the Emir of Tunis,
whose squadron was not able to effect a landing in the face of the
overwhelming numbers of the enemy. After the departure of the
Africans, the Catalonian navy formed the blockade of the port; under
the increased exertions of the besiegers the walls began to crumble,
and the inhabitants held themselves in constant readiness to repel a
storming party. It required no power of the imagination to picture the
result of a successful attack by the lawless troops now besieging the
city. The melancholy examples of beautiful and populous towns
delivered up to pillage were fresh in the mind of every Moslem in the
Peninsula. Of all the Christian armies which the Saracens of Spain
had yet encountered, that of Jaime contained the largest proportion
of foreign adventurers. The native soldiery, seldom accessible to pity,
were humane when compared with the fierce and bloodthirsty
outlaws who formed the bulk of the crusaders. These considerations
were not lost upon the people of Valencia, who could not hope to
hold in check much longer an enemy whose numbers, valor, and
military resources gave him such decided advantages over a
garrison exhausted by prolonged hostilities, whose defences were
rapidly becoming untenable, whose provisions were almost
exhausted, and which had no prospect of reinforcements or aid from
any quarter. Haunted by the dread of massacre, the Valencians
proposed terms of surrender, which the prudence of Jaime readily
induced him to accord. They were expressly guaranteed against the
violence of the troops, a provision which experience had frequently
demonstrated to be but a precarious security. Such as chose to
remain were promised the undisturbed enjoyment of their
possessions, their individual liberty, and their religious faith. All
taxes, excepting those ordinarily imposed on the people of Aragon,
were to be abolished. To those who preferred to tempt the doubtful
fortunes of voluntary exile were conceded their arms and all the
portable property they could carry, with the assurance that their
Journey through the territory occupied by the Christians might be
prosecuted without molestation. The majority of the Moslems
adopted the latter alternative. The uncontrollable temper of their
enemies, infuriated by the loss of anticipated booty and inflamed with
religious hatred, was too great a menace to be lightly braved in the
presence of men who would, under the most insignificant pretext,
indulge to satiety their ferocious instincts.
Fifty thousand persons abandoned their homes and sought
temporary safety beyond the Xucar, which was designated as the
new boundary of Christian conquest; a truce nominally of seven
years, but whose actual duration was entirely dependent on the
capricious indulgence of the victor, was agreed upon, and the royal
standard of Aragon was raised by the Moslems themselves upon the
battlements of Valencia. It required all the authority of the King to
repress the fierce passions of his unruly followers, some of whom did
not hesitate to violate the provisions of the treaty and the laws of
military discipline by attempts to plunder the helpless and the
distressed who had been compelled to yield to the inexorable results
of war. The heads of these mutineers, insensible alike to the claims
of public faith and the suggestions of humanity, were promptly struck
off by the King himself, whose evident intention to maintain inviolate
the pledges he had given produced a salutary effect on the turbulent
and insubordinate spirits of his command.
The houses and the estates abandoned by their former owners,
who preferred exile and penury to the risk of death or oppression,
were apportioned among such of the crusaders as had distinguished
themselves by the amount of their contributions, the importance of
their military service, or the number of the retainers who had
followed them to battle. Considerable difficulty was incurred in
adjusting the conflicting claims of those who, exaggerating the value
of their achievements and the generosity of their donations,
demanded an undue share of the reward. Three hundred and eighty
knights and nobles were, according to the judgment of the King,
deemed worthy of investiture with fiefs derived from the lands of the
conquered territory, whose tenures imposed upon each feudatory the
obligation of guarding for four months in every year a certain portion
of the border. The clergy, as was usually the case, secured by
superior dexterity and by the influence attaching to their sacred office
the most valuable of the lands affected by the public distribution.
Information of the surrender of the Moorish capital spread fast
through the dominions of the victorious monarch. Attracted by the
richness of the new conquest, the subjects of Jaime deserted their
barren country by thousands to fix their residence and improve their
fortunes in a land so favored by the bountiful hand of Nature. The
void occasioned by the departure of fifty thousand Moslems was
speedily filled, so far as the mere enumeration of individuals might
supply a deficiency of population. But intelligence, industry,
enterprise, and taste were not prominent characteristics of the
Aragonese and Catalonian peasantry who replaced the Moorish
merchants and artificers of Valencia. These were qualities which
could not be provided by promiscuous immigration. The new
colonists presented a striking and unfavorable contrast to the
remaining inhabitants; the numbers of the latter were eventually
reduced by systematic persecution, and the decadence of Valencia
dates from the day of its subjection to Christian authority.
The internal affairs of his kingdom urgently demanding his
attention, Jaime was forced to leave the scene of his triumph before
the political organization of the new province was complete. During
his absence, his lieutenants persistently abused their delegated
authority for the sake of private emolument. The national obligations
incurred by the conclusion of: a truce had no significance in the eyes
of these professional marauders. The King had scarcely embarked,
before a predatory inroad convinced the Moors of the duplicity of a
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