Obesity in Dogs and Cats: A Metabolic and Endocrine Disorder Debra L. Zoran, ovm, oho KEYWORDS, ‘+ Obesity + Adipocytes * Adipokines * Leptin « Adiponectin| = Cytokines # Dog * Cat Obesity is defined as an accumulation of excessive amounts of adipose tissue in the body, and has been called the most common nutritional disease of dogs in Western ccounties."~> There have been a variety of surveys reporting the incidence of obesity in various parts of the world, and in these studies the incidence of obesity ranges ‘rom 22% to 44% depending on location and criteia.®-* However, inthe past 10 years, ‘most investigators have agreed that at least 33% of the dogs presented to veterinary Clinies are obese, and that the incidence is increasing as human obesity increases in ‘the overall population.’ This statistic 's important because obesity is notjust the accu- mulation of large amounts of adipose tissue, but is associated with important meta~ bolie and hormonal changes in the body. These metabolic and hormonal changes are the focus ofthis review, and are associated with a variety of conditions, including osteoarthritis, respiratory distress, ghicose intolerance and diabetes melitus, hyper- tension, dystocia, decreased heat tolerance, some forms of cancer, and increased risk of anesthetic and surgical complications. '*"-"* Further, recent studies in a group of age-matched, pair-fed Labrador retrievers show that lean dogs have a significant increase in their median lfe span (of nearly 2.5 years) and a significant delay in the onset of signs of chronic disease. * Thus, prevention and early recognition of obesity, 28 well as correcting obesity when itis present, is essential to appropriate health care, and increases both the quality and quantity of if for pets. ‘The causes of obesity are multifactorial, and there are many genetic and environ- ‘mental factors; however, obesity is ukimately related to energy imbalance: too many calories consumed or too few calories bummed, Nevertheless, there is increasing evidence that outside factors play an important role in obesity development. One of these recognized factors is breed predisposition to obesity (ikely a genetic factor, butts is unproven}, and there are clearly other components, suchas age, sex, gonadal status, and hormonal influences that play significant roles in the development of ‘obesity. The dog breeds withincreased risk of obesity ae the Labrador retriever, Boxer, Department of Stall Animal Clinical Scences, College of Veterinary Medicine and Blomedical Stiences, Texas AM University, Colege Station, TK77845-47, USA E-mail addres: dzorancvm tare Vet cin Small Anim 0 (2010) 221-239 i-10.1016),cvsm.2008.10.008 vetemallthedinics.com 1195.5616/1015 ~ see front matter 2010 Ekevier Inc ll rights reservesm Zoran Cairn terrier, Scottish terier, Shotland sheepdog, Basset hound, Cavalier King Charles spaniel. Cocker spaniel, Dachshund (especially long-haired), Beagle, and some giant breed dogs.**"*"” However, some breeds are clearly resistant to development of obesity, with greyhounds being a notable example.’” In addition to breed-related predisposition, obesity also tends to increase with age. This phenomenon is believed ‘to result from the reduced metabolic rate that occurs with aging."* Further, Edney and Smith® reported a higher incidence of obesity in dogs with elderly owners, a phenomenon possibly related to food-, behavior-, and exercise-related factors. Obesity is more common in younger female dogs, but as both sexes reach old age (©12 years), 40% of both males and females are obese.*"*"" Another clear risk factor {or obesity is neutering; the incidence of obesity is higher in neutered dogs of both sexes. This problem is believed to be due to hormonal changes associated with neu- {ering and the reduced metabolic rate that occurs with the loss of sex hormones.°°7? ‘The reasons for this effect have been studied more in cats, but itis clear that sex hormones (and especially estrogen) ae important regulators of energy intake and metab- lism, Estrogen recently has been demorstratedto inhbitlipogenesis, andis known tobe a determinant of adipocyte number Thus, changes in sex hormones following neu- tering seem to inuence development of obesity by direct effects on the brain centers affecting satiety and metabolism (eg, the hypothalamus and others), and indirectly by atfecting cell metabolism and hotmoral regulators of food (eg, ghrelin and leptin). "7747 ‘The effect on energy metabolism is significant. A 20% decrease in energy intake was required to prevent post-spay weight gain in female Beagles.” In contrast, in a sepa- rate study of working dogs, increasing exercise after neutering also resulted in mainte- hance of ideal body condition compared with dogs that were not neutered.”° Thus, either a reduction of intake by approximately one-third, or a proportionate increase in exercise, oF a combination of both is required to prevent post-neuter weight gain in dogs. This early-age increase in body weight is a significant risk factor for adulthood obesity. Asis the case in human childhood obesity, excess weight in puppyhood pre- disposes dogs to adult obesity, and obese females between 9 and 12 months of age are +5 times more ikely to become obese as adults.” Similar kttenhood obesity study has not bean reported in cats, but similar phanomenon of weight gain following neut ing does occur in young cats, predisposing them to eavly weight gains and the hor- ‘monal changes that come with it. ther important risk factors for obesity in dogs are endocrine disorders such as hypothyroidism and hyperadrenacortcism, medications ‘thatresultin hyperphagia (anticonvulsants and glucocorticosteroids), consumption oftable scraps. treats, fre-choice feeding or poorly cortrlled meal feeding, high calorie home- cooked meals, and a sedentary lestyle that results in alack of significant exercise.” ‘The goal ofthe this review is to provide the reader an understanding of the impor- tance of adipose tissue in normal metabolism, and especially in appetite, energy balance, and glucose and fat metabolism. In addition, the role of adipokines, hormones secreted from normal white adipose tissue, are reviewed in both the normal and obese state, giving the reader an insight into the important roles of these hormones in the body. There have been several recent reviews on the nutritional aspects of obesity and the important role of diet and exercise in the management of obesity, so the interested reader is referred to these articles for more information on this aspect of obesity management.’ ‘THE ROLE OF ADIPOSE TISSUE IN NORMAL METABOLISM, Adipose tissue has traditionally been considered a diffuse, il-defined tissue with the primary role of storing energy in the form of triglyceride, and a secondary role asObesity in Dogs and Cats Insulation and protection for other body organs. In actuality, adipose tissue is a much ‘more complex organ and contains a variety of cell types (Fig. 1). In adipose tissues, there are 2 types of adipocytes: white adipose tissue (WAT) and brown adipose tissu WAT represents the majority of adipocytes in adult tissues and isthe familiar image of {at tissue: many large triglyceride-filed cells surrounded by smaller cells and struc- tures. The primary distinction between WAT and brown adipose is the presence of multilocular lipid droplets in brown fat that are actively involved in thermogenesis as a result of expression of distinct genes affecting mitochondrial function, including un- Coupling protein-1, and that are found in higher proportions in neonates.” "” Adipose tissue is made up collectively of much more than adipocytes. which account for approximately 50% of the total cell population, but includes pre-adipocytes, multpo- tent mesenchymal stem cells, endothelial cells, pericytes, macrophages, and nerve calls.°° The presence of stem cells and pre-adipocytes is crucial to the expansion of adipose tissue that occurs in obesity. These cells are recruited when existing adipo- cytes reach a critical level of hypertrophy, resulting in adipose tssue hyperplasia.” Monocytes and macrophages in adipose tissue have been identified as an important ‘contributors to obesity-related disorders because they are sources of proinflamma- ‘ory, procoagulant, and acute phase reactant cytokines adipocytes and endothelial cals also produce these cytokines) and their numbers and activity increase as adipo- cytes hypertrophy, In addition to understanding adipose tissue as a distinct organ with muttiple cell types, research in rats, mice, and humans has shown that fat in different anatomic locations have distinct biologic behavior due to local influences in gene expression and diferentition.*? In humans, itis clear that the pathologic, sequelae of obesity are influenced by the preferertial deposition of fat into visceral deposits instead of subcutaneous deposits (Fig, 2.”* This phenomenon has been termed metabolic syndrome in humans, and is associated with abdominal obesity {accumulation of visceral adipose tissue}, blood lipid disorders, inflammation, insulin Fesistance or type 2 diabetes, and increased risk of developing cardiovascular disease.*°*" A difference in secretion of adipokines from regional adipose tissue sites, ilar to that reported in humans has been reported in cats and dogs.°®** but a true Small structures surrounding and interspersed between the triglyceride-fled adipocytes are primarily macrophages and vessels. (8) Electron micrograph of visceral white adipose ‘esue showing the Ultrastructure of the nucleus of an adipocyte with multiple smal fat-con- taining bodies, which are new adipocytes prior to being released. (Courtesy of Mr Ralph NNicholes and Dr Fred Clubb, Texas Heart institute, Houston, TX) 23228 Zoran Fig. 2. (A) Magnetic resonance image {T1-weighted) of 2 nermal dog (body condition score 4/9 illustrating the normal steuctures and small amount of intra-abdominal body fat. (8) Magnetic resonance image (Ti-weighted) of an obese dog (oady condition score 8) illus: trating the large amounts of intra-abdominal fat. The Image has been colorized to improved visualization of organs versus adipose. (Courtesy of Washington State Univesity College of Veterinary Medicine, Pullman, WA; with permission} ‘metabolic syndtome has not been described in these animals, ikely, in part, due to differences in risk factors for cardiovascular disease and blood lipid abnormalties {An important aspect of adipose tissue function was unknown until the mid-1880s With the discovery that WAT was the source of the hormone leptin. Since that time, WAT has become known as an important endocrine organ that secretes a wide variety of substances, including steroid hormones, growth factors and cytokines, eicosa- roids, complement proteins, binding proteins, vasoactive factors, regulators of lipid and glucose metabolism, and others active in energy metabolism and appetite control Fig. 3).°" The many hormones and factors secreted by adipose tissue have become collectively known as adipokines. Adipokines are essential to normal physio- logic function, and are important in the regulation of diverse biologic processes including eneray balance, glucose and lipid metabolism, inflammation and immune function, hemostasis, vascular function, and angiogenes's.*°“° There are more ‘than 50 known adipokines. Of these, the most well known is leptin, but others, such a adiponectin, resistin, and some of the proinflammatory cytokines, for example, interleukins (1), tumor necrosis factor alpha (TNFa), interferon gamma (IFNy) and so forth, have been studied in multiple species, including dogs and cats. LePTIN Leptinis the prototypical adipokine, and ofall of the adipokines isthe one best charac- terized in dogs and cats.*°*~ Leptin is a protein encoded by the ob gene, and although adipocytes are the main site of production, leptin mRNA can be found in placenta, mammary gland and liver in humans and rodents.“* Although leptin Is secreted constitutively by adipocytes, increased secretion is based on the energy ‘lux within these cells, and circulating concentrations of leptin correlate with fat mass.“* This correlation is true in all species examined to date, including dogs and cats.**3*” Transcription of the ob gene and secretion of leptin are also controlled byObesity in Dogs and Cats ar = Zs, neve a Fig. stration of white adipose tse WAT adipogtes showing and Some of the hormanes and cytokines secreted by this tisue. This illustration is not representative of all adipocytokines known to be produced by WAT. ASP, acylation stimulating protein: IG, insulin-like growth factor, MCP, monocyte chemotactic protein; MIF, macrophage inhibitory factor, NGF nerve growth factor, PA, platelet activator inhibitor; PG, prostaglandin; sR, serine receptor, SAA, serum amyloid A: TGF, tumor growth factor; VEGF, vascular endothelial growth factor. llustration by Mr Larry Wadsworth, Texas A&M University, College Station, ™) 2 variety of metabolic and inflammatory mediators, including insulin, glucocorticoids, endotoxin, and such cytokines as TNF, IL1, andIL-6.°°° Theeffects ofleptin ave initi- ated, as with many adipokines, through interaction wihits receptor. The leptin receptor ‘amily (Ob-A) is very closely related to members of the IL-6 family of receptors, and although the highest numbers of receptors are expressed in the satiety centers of the hypothalamus, they can be found widely distributed throughout the body. reflecting lep- tin’s involvement in the regulation of civerse physiologic processes. **-°° \Wnen leptin, which is from the Greek “leptos” for thinness, was discovered, its primary actions were believed to be suppression of appetite and increased energy expenditure (via thermogenesis).*"“*** These early reports were based on mouse ‘models showing that absence of leptinresultedin severe obesity." Subsequent studies have shown that leptin binding to its receptor in the hypothalamus results in a series of events leading to suppression of appetite, including stimulation of anorexigenic heurons Via neuratransmitters such as cocaine- and amphetamine-regulated transcript (CART), and melanocyte-stimulating hormone (MSH), suppression of orexigenic neurons (via neurotransmiters such as neuropeptide Y and agout-related peptide), land suppression ofthe release of endocannabinoids, which are regulators of orexigenic neurons. hough itis clear that leptin deficiency (ether due tolack ofthe hormone orits receptor) results in development of severe obesity in rodents and humans, itis not ‘a common cause of obesity in humans and has not been documented to date in dogs or cats. Rather, the majority of obese humans, and dogs and cats as well, have high Circulating concentrations of leptin, and the problem isnot leptin deficiency but dimin- ished end-organ response to leptin in the hypothalamus. Thus, obesity unrelated to specific genetic mutations in leptin or its receptor is characterized by leptin resistance and hyperleptinemia. Of note, hyperleptinemia in humans can also occur as a conse~ quence of aging (independent of or disproportional to increases in body fat mass), but this phenomenon has not yet been reported in dogs or cats.°*” Unfortunately, ‘the causes of leptin resistance are likely multifactorial, which make identiication and26 Zoran reversal of the problem difficult. Also important, leptin resistance results in blunting of ‘the satiety effects of the hormone on the hypothalamus and concurrent lowering of the body's eneray metabolism, thus abetting further weight gain (or at least making Woight loss extremely dificul) and predisposing obese subjects to development of other metabolic abnormaities associated with leptin dysfunction. Current research suggests that the blunted response to leptin may be due, atleast in part, to saturated transport systems for leptin across the blood-brain barrier or defects in signaling in ‘the hypothalamus, * and that leptin resistance is selective: peripheral leptin receptors continue to function and this may be important in the pathogenic metabolic effects of hyperleptinemia in obesity in humans wth metabolic syndrome," Leptin is involved Innnormal reproductive and immune function, and modulation of insulin sensitivity, and generally seems to be proinflammatory (mediated by IL-6 and others), prothrombotic, prooxidant, and has opposite effects to adiponectin, Thus, as with many hormonal and metabolic systems, a balance is achieved between the proinflammatory and anti-inflammatory effects of 2 hormones produced in adipocytes, leptin and adiponec tin, and when the balance is disrupted due to development of obesity, it results inhyper- leptinemia, leptin resistance, and development of obesity-related disorders. Leptin in Dogs and Cats Circulating concentrations of leptin correlate with fat mass in bath dogs and cats “= ‘Thus, increased fat mass, from either experimentally induced obesity or in pet dogs and cats with increased body condition scores, results in predictable, measurable increases inleptin. In contrast, reduction in fat mass also results a decrease in leptin concentrations in both species."™"" There is ob gene expression in dog pre-adipo- cytes and mature adipocytes trom WAT ftom multiple sites, but no expression in tissues other than WAT—a finding that has only been observed in the dog *” Studies of ab gene expression have not been reported in cats. In both dogs and cats, leptin concentrations are increased after a fatty or high-energy meal. In dogs, this effect can result in 2- to 9-old increases of leptin concentrations for as long as 8 hours.®* Of note, in cats the postprandial effect of dietary composition on leptin concentration is not consistent, but seems to be modulated by the relative insulin resistance and body fat mass.®* Regardless of body condition score and fat mass, cats with insulin resistance (eitner due to cet or other causes) have higher circulating concentrations of leptin than cats with normal sensitivity to insulin.”” Thus, the role of leptin in feline metabolism is clearly liked to insuin sensitivity and glucose metabolism. The issue of breed:-related influences on metabolism and obesity is unsettled, primarily due to 2 paucity of published studies; however, results of a recent study by Ishioka and colleagues,® show that the breed of dog may infuence leptin concentrations. For example, when examined within body condition score groups, Shetland sheepdogs had higher circulating leptin concentrations, whereas dachshunds, Shin Tzu, and Lab- rador retrievers had lower concentrations.© No specific breed-elated studies on lep- tinhave been reportedincats, Another factor affecting leptin concentrations in dogs is glucocorticostero therapy (eg, dexamethasone increases leptin concentrations in dogs, but prednisone seams to have no effect) and this may also influence feeding status, energy regulation, and other aspects of metabolism.**”? Finally, the effect of neutering on body weight and leptin status in cats has been a topic of considerable interest. In general, increases in leptin occur after neutering in cats, and are correlated with the amount of body fat gained post-neuter, and this effect occurs in both males and females.” "* The increases in leptin likely reflects the strong tendency for cats to gain weight post-neuter i their food intake is not closely regulated. Further studies, are required to assess the role of neutering on body fat in catsObesity in Dogs and Cats ‘ADIPONECTIN After leptin, the next most studied and well-understood adipokine is adiponectin. When adiponectin was discovered (after the discovery of leptin in the mid-1990s), a variety of dtferent names were ascribed, including Acrp 30, GBP28, and AdipoQ.”* Unlike leptin, adiponectinis produced exclusively by mature adipocytes, after which it circulates as trimers, hexamers, or even high molecular weight multimers in very high concentrations. Adiponectin is among the most highly expressed genes in adipose tissue.” Adiponectin secretion is stimulated by insulin as well as by several drugs (eg, thiazolidinediones, and cannabinoid-1 receptor antagonists such as rimonabant) and dietary constituents (eg, fish oil, inoleic acid, soy protein).”°~”* These effects have rot yet been reported in dogs or cats, Nevertheless, the role of adiponectin is tightly connected to glucose metabolism through enhancing insulin sensitivity and increasing glucose uptake via the GLUT 4 transporter.’ In addition, adiponectin increases alycolysis by phosphorylation of phosphotructokinase and increases fatly acid oxida~ tion, 2 functions that also are essential to enhanced glucose uptake and metabolism." Inhumans, other well-characterized effects of include its anti-inflammatory properties (which are opposite of leptin) and inhibition of the development of atherosclerosis. "? The beneficial cardiovascular etfects of adiponectin may stem from its function as fa vasodilator, an effect mediated through adiponectin’ promotion of increased expression of endothelial nitric oxide synthase (INOS) and prostacyclin synthase.*?** ‘The antiinflammatory effects of adiponectin seem to be due to the abily of the hormone to suppress TNFa production by macrophages.*® Although these effects are being widely studied in humans, there are no reports yet in dogs or cats conftming similar physiologic effects in these species. Inthe obese state, leptin concentrations are typically dramatically increased, reflecting the large increases in fat mass and leptin secretion. However, unlike leptin, increases in {fat mass result in decreased concenivations of circulating adiponectin, and conversely, weight loss results in a return to normal adiponectin concentrations.** Furthermore, in humans adiponectin concentrations are negatively correlated with body fat mass, fasting insulin concentrations, and plasma triglyceride concentrations.*” The mechanisms Lundertying this decrease in aciponectin are unknown, but changes seem to occur at 3 levels: decreased total adiponectin production (whichis greatest with visceraladiposit), changes in relative proportions of the molecular weight forms of adiponectin fewer high ‘molecular weight forms are present in obese individuals), and changes inthe expression ‘of aiponectin genes (proinlar»matory cytokines IL-6 and TNF: in the enlarging fat mass are inhibitors ofthese genes). ** Inhumans, decreased circulatinglevels of adjoonectin are linked to development of type 2 diabetes, insulinresistance, hypertension, and devel- ‘opment of progressive ventricular hypertrophy,""° and although these syndromes are commonly associated with obesity, the persistent reduction in adiponectin concentra- tions present even in persons matched for body mass and adiposity suggests that low Circulating adiponectin concentration is an independent risk factor for development of ‘metabolic complications. Adiponectin in Dogs and Cats ‘Adiponectin nucleotide and amino acid sequences have been determined in both dogs and cats, and show strong homology t those of other species,"!~ while canine adiponectin appears to circulate as variably sized complexes similar to human aclipo- nectin. As in humans, both canine and feline adiponectin‘ highly expressed in WAT, and in cats the gene is expressed insignificantly greater amounts in visceral adipose sito.” Similar to humans, both dogs and cats have lower circulatng concentrations ar28 Zoran of adiponectin with increased fat mass, and in dogs the gene expression is also decreased (this is not yet been studied in cats)."*”* Studies in dogs and cats inai- cate that adiponectin is predictably decreased in the obese state, suggesting that this hormone may have similar roles in the development of the metabolic changes, insulin resistance, and ype 2 diabetes. Further work is needed to define the role of adiponec- tin in the development of feline diabetes, the incidence of wnich has greatly increased in recent years RESISTIN Resistin was originally discovered as an adipokine secreted by murine adipocytes. ‘This hormone is also found in human adipocytes, as well as in adipose tissues of cattle and pigs. To date, expression of resistin has not been documented in dog or cat adipocytes, but the technical issues of assay development have been profound, and this may have slowed this discovery. In addition, the resistin receptor has also not yot been found. Thus, a great deal of work is needed to further define the presence and role of this adipokine in domestic animals and humans. However, the secretion of this hormone in rodents seems to follow leptin: circulating concentrations increase ‘with increasing fat mass and following a meal. Hyperresistinemia results in develop- ‘ment of insulin resistance and metabolic derangements typical of type 2 diabetes. ** Increased concentrations of resistin are associated with proinflammatory eytokine secretion by macrophages, and in humans, increased resistin concentrations are correlated with atherosclerosis,” Additional work is required to fully understand the role of this adipokine in obesity-related disorders, especially those associated with dysregulation of glucose and development of insulin resistance. ANGIOTENSINOGEN AND THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM. One of the best known metabolc/regulatory systems inthe body isthe renin-angio- tensin-ldosterone system (RAAS) ands importance in vascular homeostasis, water balance, and renal functonis well documented. Thus, the recognition that RAAS plays an importantrole in normal adipocyte biology, and particularly in adipocyte citerertia- tion and metaboism, was acrucial discovery."° WATis amajor source of angiotensino- genin humans and rodents, second ony tothe livarin concentrations ofthis precursor {oangiotensinl Infact, renin and angiotensin-converting enzyme are presentinhigh concentrations in fat as well andthe local production of angiotensin lin adipose tssue seems to play a role in normal adipocyte ditferentiaton, size, and insulin sens tity.°7°" I obese humans, increased production of angiotensinogen is a major contributor to the development of cardiovascular and kidney disease, Increases in angiotensinogen from adipocytes result in increased circulating concertrations of angiotensin I, which promotes increased vasoconstrictor actvty (which can lead to hypertension orrenal dysfunction), andincreased concentvations of aldosterone, which promotes renal sodium retention. '°°-" Studies in obese rodents show that dysregu- lation of the RAAS system ultimately leads to reduced renal boo flow and glomerular {tration as well as to development of hypertension, both potentially very harmful to kidney function and development of renal cisease."*™"? As with resistin, the role of the RAAS system in adipocytes and in obesity in dogs and cats isnot well understood. Only one study has documented the activation of the RAS in det-induced obesity in dogs, and in that study the focus was onthe effects of RAAS activation on functional and structural changes in the kidney as a model of human disease." Based on the importance of RAAS in obesiy-associated diseases in humans and rodents, the role of RAAS in obese dogs and cats may also be importantObesity in Dogs and Cats INFLAMMATORY CYTOKINES (INTERLEUKINS, TNFa, CHEMOTACTIC ‘AND COMPLEMENT PROTEINS) Obesity is considered to be a chronic inflammatory disease. In humans, the inlamma- tion associated with obesity is known to cause ineulin resistance, dyslipidemia (increased plasma triglycerides, decreases in high-density lipoprotein [HDL|-choles- terol, increases in low-density lipoprotein (LDL-cholesterol), heart diseases (including atherosclerosis, hypertrophic cardiomyopathy, and heart falure secondary to the increased preload and afterload as a result of hypertension and fat mass), increased risk of hypertension and stroke, and osteoarthritis,"°*" In normal-weight individuals, concentrations of proinflammatory cytokines secreted by adipose tissues are low or lundetectable. However, in obesity, adipokine production is dysregulated, resulting in increased production of proinflammatory cytokines, while increased numbers of macrophages, which also secrete cytokines that promote the inflammatory process, are recruited to adipose tissue." Although a wide variety inflammatory cytokines are produced by adipose tissue, TNFa and IL6 are the most widely studied cytokines produced by adipose tissue in any species, including dogs and cats.°°°* TNFa. was originally named for its ability to induce the necros's of cancers after acute bacterial infection. However, this cytokine is actively involved in many processes, including inflammation, autoimmune diseases, tumorigenesis, viral replication, septic shock, ‘ever, and obesity" TNFa, was frst shown to be involved in adipocyte metab- lism by suppressing the expression of many adiposespecific genes, such as lipopro~ tein lipase, and by stimulating lipolysis."°” More recently, TNFa was found to have an important role in the development of insulin resistance as a resul ofits abilty to down- regulate GLUT 4 in adipose tissue."°* Subsequent studies in rodents have proven a role of TNFa in the development of insulin resistance, but human studies attempting to neutralize the effects of the cytokine have shown less compeling improvements in insulin sensitivity, Thus, the complete role ofthis cytokine in the development of insulin resistance remains to be discovered. The interiaukins, and specifically ILS, soem to have a significant role in obesity-associated inflammation in all species studied to date. In humans, serum concentrations of IL-6 are increased in type 2 diabetes and in metabolic syndrome, and correlate with an increase in body tat mass.” Some of the effects of IL-6 secreted from adipocytes include stimulation of hepatic triglyceride secretion, inhibition of insulin signaling in hepatocytes, and induction of hepatic C- reactive protein synthesis.”*°* WAT is also a source of a variety of ather inflammatory cytokines, incluging IFN-y, other interleukins (IL-1, -8, -10, -18), C-reactive protein, monocyte chemotactic protein-1, and complement proteins, such as platelet activator inhibitor-1, Factor Vil, and tissue factor (see Fig. 2)**2”°2%4%° In short, the chronic, subacute state of inflammation that accompanies the accumulation of WAT has been ‘documented by the increases in circulating concentrations of inflammatory matkers, and ig further evidence that obesity-induced inflammation plays an important patho- genic role in the development and progression of obesity-related disorders. INFLAMMATORY ADIPOKINES IN DOGS AND CATS Studies in dogs have only recently begun to document the role of proinflammatory cytokines in the pathogenesis of obesity and obesity-related disorders in this species. Using reverse transcriotion-polymerase chain reaction to detect the mRNA of adipo- kines in dog adipocytes, investigators have detected genes for angiotensinogen, plas- ‘minogen activator inhibitor-1, IL-6, haptoglobin, metallothionein-1 and -2, and nerve growth factor in adipocytes of WAT.’ Other investigators, in a study of experimentally induced obesity in dogs, reported increases in TNFa, insulin-like growth factor, and 229230 Zoran ronesteriied fatty acids that were found concurrently with increased body fat mass and decreased insulin sensiity.“” Both of these studies miror results in human and rodent studies, and suggest that obesity in dogs has many of the same physio: logic and pathologic characteristics previously described in these species. Anothi study in obese dogs found that although the dogs developed biochemical evidence of insulin resistance, instead of having increased concentrations of C-reactive protein, concentrations were decreased significantly, This finding contrasts with those of studies in humans in which C-reactive protein concentrations increase in obesity." Finally, studies of proinflammatory cytokines in feline obesity are lacking. UNDERSTANDING OBESITY AS A DISEASE Obese humans generaly donot lve as long as their lean counterparts, and are much more likely to sufer from obesity-related ciseases."™""* Dogs and cats are suscep- ‘ible tothe same detrimental efecs, including decreased longevity, and development ofa variety of cisorders that are also associated with human obesity (Box 1)” Dietary calorie restriction to maintain alean body condition significantly increased longev'ty in 2 group of 24 Labrador retrievers. In that study, the dogs in the energy-restrcted group were fed approximately 25% less than their pal-fed counterparts (another group of 24 dogs), which were alowed to become overweight or obese. The lean dogs lived an average of 2 years longer than ther overweight counterparts, and had reduced incidences of hip dysplasa, osteoarthritis, and glucose intolerance as well. ‘This study and others ilustrate that obesity is clearly associated with increased morbidity (n this study morbidity was associated with osteoarthritis) and early mortaity."""*""® Heat intolerance, increased anesthetic risk, increased dificuty routine cnical procedures (catheter placement, palpation, imaging), and pro- longed surgical procedures have also been documented in obese dogs."2” Untl recently, however, there were few studies in dogs, and even fewer in cats, that ilus- ‘rated the increased disease risk associated with obesity {As In humans, obesity in dogs and cats is associated with a variety of endocrine abrormaities. The most widely recognized and studied example is insulin resistance and the increased risk of development of type 2 diabetes."*“” The problem of obesity induced insulin resistance s increasing in cats concurrent withthe inerease in type 2 diabetes in cats over the past 10 years.” In dogs, however, subclinical glucose intol- erance and insulin resistance is often present without over signs of ciabetes. n addi- tion tothe hormonal eects of obesity on insulin function, there isan increasing body of evidence showing that obesity has a profound effect on thyroid hormone function. In one study, 42% of obese dogs had biochemical evidence of hypothyroidism (low serum free Ts gra concentrations, high serum thyrotropin [TSH] concentrations. or both), and of those doge, a large percentage had no other clinical signs of hypothy- roicism (similar to a phenomenon in humans termed substnical hypothyroidism, in hich TSH increased and Tis ether normal or decreased. However, in an earlier Sludy assessing the role of thyroid hormone in canine obesity the onl differences observed were in total T, and total, concentrations, which were highern the obese diogs.""® This may occur as a resuit of thyrold hormone resistance, but no studies, support this. Of note, in a study of obese cats, 1T, concentrations increased signif cantly (some increases were within the normal range), and the increase was propo!- ‘ional o the increase in nonesterified fatty acids (NEFAs) tre fatty acids increase in feline obesity), a finding that may indicate that thyroid hormone uptake at the celular levels inhibited by the presence of high concentrations of NEFAs."” Further clarifiea- tion of the effects of obesity on thyroid hormane function is needed before specificObesity in Dogs and cats 231 Text Disorders associated with obesity Orthopedic disorders Oneoartits Fractures (primarily humeral cones) Cruciate igamenttearsrupture Intervertebral dik disease Joint disorders Endocrine and metabolic clisorders Hyperadrenecortcim Hypothyroidism Diabetes melita Hypopituit Hyperipideria Ghicose intolerance Hepatic lipidosis cas) Cardiac and respiratory lsorders Picklckian syndrome Tracheal collapse Laryngeal paralysis Brachycephalic away syndrome Reduced airway compliance Urogenital izorders Urotthiassfealium oxalate) Urethral sphincter mechanism incompetence “Transitional cel carcinoma Mammary neoplasia Dystocia IMiopathic itis Other miscellaneous disorders Heat intolerance Exercize intolerance Increased anesthetic ritk Reduced life span recommendations can be made; however, obesity seems to have a significant infu- fence on thyroid hormones and their celular function Dyslipidemias (alterations in cholesterol, triglycerides, and NEFAs) are commonly associated with obesity in humans, and in fact are one of the components of the meta- bolic syndrome. To date, only a few studies have been performed in either dogs or cats that further define changes in serum lipids in these species. However, one2 Zoran cross-sectional study in dogs evaluated the effect of abesity on serum concentrations of glucose, cholesterol, HDL-cholesterol, triglyceride, and on alanine aminotrans- {erase activity, and found that significant increases in serum triglycerides and total cholesterol occurred in obese dogs.’"* These findings were confirmed in another clin- ical stuay assessing the utity of a bioelectic impedance device for assessment of body fat in dogs. In that study, serum cholesterol and triglyceride concentrations were also significantly higher in obese dogs than in lean dogs.""? Another study of cats fed to achieve long-term obesity revealed similar changes in plasma lipids similar to those seen in obese people. Obese cats had increased NEFAs and triglycerides, decreased HDL, increased LDL, and overall increases in total cholesterol, and these changes occurred irrespective of diet."2° In bath dogs and cats, obesity seems to cause significant changes in lipid and lipoprotein metabolism that may be important in the development of other obesity-associated diseases, (Obese humans are prone to development ofa variety of respiratory syndromes and airway distress, ranging from increased episodes of asthma to difficulty breathing due 10 Pickwickian-type obstruction of thoracic movement."?112° Few reports of similar conditions have appeared that address the effects of obesity on respiratory function in dogs or cats. However, there have baen widespread anecdotal reports of obesity Creating greater distress for dogs with tracheal colapse, laryngeal paralysis, and cats with asthma, suggesting a possible association. More evidence of the deleterious effects of obesity on the respiratory system have recently begun to surface, with the observations that obesity causes expiratory airway dysfunction in dogs." In that study, normal breathing was unaffected by body condition, but in obese dogs (body condition score 9/9) during hyperpnea, expiratory airway resistance was markedly greater, indicating a dynamic flow limitation in these dogs that likely occure in the distal airways." No other abnormaities in airway function were observed. Further studies are needed to determine whether these changes are due to increases in inflammatory cytokines from obesity or due to alway wall resistance from decreased compliance. In either case, this study demonstrates that airway dysfunction, though subctinial in the majority of dogs, can occur. Studies of respiratory function in obese cats have not been published. ‘TREATMENT OF OBESITY ‘The management of obesity in dogs has long been focused on reducing energy consumption (dietary management) and increasing energy expenditure (exercise). This therapeutic approach is very effective when it's implemented completely and early’; however, t can be quite dificult to overcome the behavioral, social, meta- bolic, and hormonal influences of obesity in many dogs and cats. In humans, obesity management options inclide dietary management, exercise, behavior modification, pharmacologic therapy, and surgery. At this point, surgical therapy for obesity in ‘dogs and cats has not been reported. For cats, there are currently no safe pharmaco- logic treatments for obesity, and until recently the options for dogs were limited to ‘those products that reduced intestinal absorption of fat—a less than ideal approach with @ significant therapeutic downside—and drugs that increased sympathetic tone, and were generally ineffective or potentially harmful” Dirlotapide(Slentro) is a newer drug that is effective in treatment of obesity in dogs. ‘The rug isa selective (intestinal) microsomal riglyceride transfer protein (MTP) inhio~ itor. Dirlotapide reduces the absorption o ft from the small intestine by slowing the packaging of fatty acids and protein into chylomicrons, a process driven by MTP activity in the cytoplasm of the enterocyte. As a result of MTP inhibition, there isObesity in Dogs and Cats 2 reduction in fat absorption from the small intestinal lumen, but this is responsible for nly a small fraction (approximately 10%) of the effect of dirlotapide on weight oss."** Further, because the fat is absorbed into the enterocyte, steatorrhea and other side offects related to fat malabsorption are minimal. Intracellular accumulation of fat ddue to MTP inhibition triggers release of peptide YY from the enterocyte into the systemic circulation." Peptide YY is a potent appetite suppressant and satiety hormone, and is one of the peripheral hormones responsible for signaling the hypo- ‘thalamus and other brain centers to control intake. The primary effect of dilotapide is reduction in appetite. In clinical tals and in ciont-owned dogs, diotapide typically ‘a causes reduction in food intake of about 10%.'*! The key benefit of adding dirlota- pide to a weight loss program is that it influences one of the major obstacles to successful weight loss: it helps to control food intake. And although itis important to recognize that successful management of obesity requires appropriate dietary and exere'se regimens, dirlotapide can be an effective tool in to the treatment of obesity SUMMARY Obesity is the most common nutritional disorder of dogs and cats in Westem coun- ‘ties. Although obesity is caused by an imbalance between energy intake and energy expenditure, there are many factors, both environmental and genetic, that influence this balance. Further, the alarming increase in obesity is important because this condi- tion is associated with important metabolic and hormonal changes in the body, The systemic metabolic and hormonal changes that occur in obesity are the result of dys- regulation of the adipokines secreted by WAT, and are the key factors in many diseases and disorders associated with obesity. The list of concitions associated ‘with obesity is increasing as new research identifies the relationships between proin- ‘flammatory adiookines and disorders such as osteoarthritis, respiratory distress, dia- betes melitus, hypertension, dystocia, heat intolerance, and some forms of cancer. Because of the seriousness of obesity as a metabolic, hormonal, and inflammatory disease, prevention and management of obesity is essential REFERENCES 1, German AJ. The growing problem of obesity in dogs and cals. J Nutr 2006;136: 19408-88. 2. Gorman AJ, Holden SL, BissotT, et al. 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