Obesity and diabetes mellitus are reaching epidemic proportions in humans throughout the world, and this crisis is reflected in the pet population. The prevalence of overweight and obese cats in the United States has increased almost 30% during the past 25 to 30 years.1,2 This dramatic increase in obesity coincides with an increase in the rate of diabetes mellitus among pet cats. In North America, prevalence of diabetes in cats has increased from 8 cases/10,000 cats in 1970 to 124 cases/10,000 cats in 1999.3 Because more pet cats are becoming overweight, it is important for researchers and veterinarians to focus on new preventive and treatment measures for obesity and diabetes in cats. Reviewing the literature on research in humans and rodents will enable clinicians and researchers to understand the complex physiologic processes of obesity and apply this knowledge to affected cats.
During the past 15 years, immense research efforts in human medicine have focused on obesity as a disease and the role of adipose tissue in the pathologic process of obesity. Adipose tissue is an endocrine organ, and nearly 100 proteins are secreted by adipocytes.4 Proteins, hormones, and cytokines derived from adipose tissue are called adipokines. Although many adipokines have been discovered, extensive research has been conducted on only a handful of physiologically important compounds. Among these are leptin, TNF-α, and adiponectin.
Leptin
The name leptin is derived from the Greek word lept's, which means thin, because injection of the hormone into leptin-deficient and clinically normal mice results in reductions of food intake and body fat.5 The main physiologic role of leptin is to regulate body fat mass through satiety and energy metabolism. As body fat mass increases, more leptin is secreted by adipocytes.6 The arcuate nucleus of the hypothalamus is the most commonly recognized site for leptin action, and this region of the brain contains neurons that both stimulate and suppress appetite.7 Leptin inhibits neuro-transmitters that increase food intake and lower energy expenditure and activates neurons that suppress appetite and increase energy expenditure.8,9 As a result, leptin reduces appetite and increases energy expenditure when adipose concentrations increase. Leptin has been termed a lipostat because it acts like a thermostat for body fat mass.10
Although increases in concentrations of leptin should reduce body fat mass, obese individuals often have the highest concentrations of this hormone.11 Leptin resistance is the condition when leptin cannot effectively regulate appetite and energy expenditure.12 The consequences of leptin resistance have been described in a clinical study13 in which leptin was administered at a dose 20 to 30 times higher than normal physiologic concentrations to induce significant weight loss in obese human subjects. Cats may also have leptin resistance. In 1 study,14 16 neutered adult cats gained an average of 44% of their body weight, and mean leptin concentrations tripled from 7.9 to 24.5 ng/mL. Despite the high concentrations of leptin, the overweight and obese cats (body fat ranged from 34% to 48%) continued to eat and gain weight. In another study15 of 19 sexually intact cats, overweight and obese cats had high concentrations of leptin. Analysis of the results of these studies suggests that despite higher leptin concentrations, the ability of leptin to maintain ideal body weight in overweight and obese cats is impaired.
Although the primary physiologic role of leptin is to regulate storage of body fat, it has a myriad of effects on the immune, cardiovascular, and reproductive systems. Leptin may also enhance insulin signaling to improve intracellular glucose uptake and decrease the accumulation of lipid in peripheral tissues.16 Lipid accumulation in cells can lead to lipotoxicosis, which has been implicated in the development of peripheral insulin resistance.17,18 Administration of leptin decreases cellular lipid stores in pancreatic, adipose, hepatic, and cardiac tissues of rodents.19 Leptin deficiencies in ob/ob rodents result in obesity, insulin resistance, and diabetes.20
Although there is evidence to confirm positive effects of leptin on insulin sensitivity, results of another study21 suggest that leptin has little effect on insulin performance or could even be detrimental to insulin signaling. The paradoxic effects of leptin on insulin sensitivity may be attributable to selective leptin resistance. Centrally, leptin appears to facilitate whole-body glucose disposal by stimulating satiety, increasing energy expenditure, and affecting the autonomic nervous system. If the central effects of leptin are blunted and overall leptin concentrations increase, the insulin-inhibiting effects on peripheral tissues would become more prominent. This idea is supported by in vitro evaluations that have revealed detrimental effects of leptin on insulin action, whereas in vivo evaluations have indicated that leptin has an insulin-sensitizing role.22
Although the data from studies on leptin in cats is only a small fraction of the data available from studies on leptin in humans and rodents, the results for cats are consistent with those of other species. Leptin correlates positively with body fat mass in cats.14,15,23,24 In a study25 in which investigators evaluated lean and overweight cats, high concentrations of leptin were strongly associated with insulin resistance, independent of the degree of adiposity. Diet composition appears to have little influence on leptin concentrations in cats. In another study24 in which effects of high carbohydrate–low protein diets were compared with effects of low carbohydrate–high protein diets, serum leptin concentrations did not differ between groups. The percentage of dietary fat also has little impact on leptin concentrations in cats.26
The influence of reproductive hormones and sex of an animal on leptin concentrations in cats is not completely clear. In 1 study27 of 8 cats, gene expression of leptin in adipose tissue decreased after ovariohysterectomy. These cats were fed to maintain presurgical body weight, and biopsy specimens of adipose tissue were collected before surgery and 12 weeks after surgery. Decreases in leptin gene expression and subsequent decreases in serum leptin concentrations could contribute to weight gain typically found in spayed cats.2 However, in a study26 of 24 adult male and female cats that underwent gonadectomy, leptin concentrations did not change significantly after surgery. In another study23 in which 7 male cats were allowed to naturally gain weight for 44 weeks after castration, body weight and leptin concentrations both increased. This finding was in accordance with results of a study28 that involved 32 clinically normal and lipoprotein lipase–deficient male cats. When 16 of the cats were neutered, body weight and leptin concentrations increased, compared with results for the 16 sexually intact control cats. Although both of these studies23,28 indicated that leptin concentrations increase after castration, body fat mass was not controlled and leptin presumably increased secondary to expanding body fat mass. However, in a study29 in which 10 male and 10 female cats were gonadectomized and then fed a diet designed to maintain pregonadectomy body weight, leptin concentrations increased significantly in males after surgery but were unchanged in females.
Although administration of leptin appears to be ineffective for weight management in severely obese human patients, it still holds potential for use in overweight animals that have not developed leptin resistance. There currently are no approved weight-loss drugs available for use in cats; thus, additional research on leptin resistance and the pharmacologic potential for leptin could provide more options for managing obese cats.
TNF-α
Tumor necrosis factor-α is an inflammatory cytokine expressed by a variety of cells, including macrophages, mast cells, neuronal cells, fibroblasts, and adipocytes. Obesity increases migration of macrophages into adipose tissue, and this contributes to increased TNF-α expression by fat depots.30,31 One theory behind the recruitment of monocytes and macrophages into expanding adipose tissues is that an increase in apoptosis and necrosis of adipocytes yields chemoattractant agents.32,33
Key differences in secretion of TNF-α by adipose tissue exist among species. In mice, TNF-α is released into the systemic circulation,34 whereas in humans, most adipose-derived TNF-α is secreted locally to exert paracrine and autocrine actions.35,36 Although circulation patterns of adipose-derived TNF-α are not clearly defined in cats, mRNA expression within fat increases dramatically with obesity.37,38 Analysis of samples of adipose tissue collected from 10 obese and 8 lean adult neutered cats revealed that TNF-α mRNA expression, as determined by normalization on the basis of results for feline β-actin, was significantly (P < 0.03) higher in the obese cats (mean ± SD, 11.2 ± 5.6 arbitrary units) than in the lean cats (1.7 ± 0.3 arbitrary units).38 In another study,37 concentrations of TNF-α detected by use of an ELISA were also higher in adipose tissue of obese cats, compared with concentrations in adipose tissues of lean cats.
A primary action of adipose-derived TNF-α is induction of localized insulin resistance. Tumor necrosis factor-α downregulates genes and inhibits transcription factors that regulate insulin sensitivity.39 Furthermore, TNF-α also impairs triglyceride storage and induces lipolysis in fat tissue.33 This results in release of more free fatty acids into the circulation.35 High concentrations of serum free fatty acids diminish insulin sensitivity in peripheral tissues.40 Tumor necrosis factor-α can also alter secretion of other adipokines involved in glucose metabolism. In particular, TNF-α is inversely correlated with adiponectin and alters its gene expression.33,34,41,42
Adiponectin
One of the most intriguing and metabolically important adipokines is adiponectin. Although adiponectin is released from adipocytes, higher amounts of body fat actually lower serum concentrations of adiponectin. Therefore, overweight individuals have lower circulating concentrations of adiponectin than do lean individuals.43 The reason for this paradoxic relationship is not clear. Size and insulin sensitivity of adipocytes may affect adiponectin production. As adipocytes swell and increase in size, they become more insulin resistant and secrete less adiponectin in vitro.44 In addition, hormones such as testosterone and inflammatory cytokines such as TNF-α negatively impact adiponectin production.45,46
The basic component of adiponectin is a 30-kDa molecule that combines with similar molecules to form 90-kDa trimers. These trimers are referred to as low–molecular-weight forms of adiponectin.44 Low–molecular-weight forms of adiponectin can also combine to yield middle–molecular-weight and HMW forms of the hormone. The HMW form consists of 12 or more adiponectin molecules bound together, and studies47,48 have revealed that decreases in concentrations of the HMW form are more closely associated with insulin resistance and diabetes than are concentrations of total adiponectin or the lower-weight forms.
Adiponectin exerts anti-inflammatory and cardioprotective effects in humans.49 However, the most influential role of adiponectin is as an insulin sensitizer. Adiponectin is closely associated with insulin sensitivity, independent of body fat mass.50–52 In a study53 of obese rhesus monkeys, low adiponectin concentrations were correlated with insulin resistance and preceded the onset of diabetes. Prospective and longitudinal studies54–56 in humans also indicate that lower adiponectin concentrations are closely associated with insulin resistance and the subsequent development of diabetes.
The overall effect of adiponectin in skeletal muscle is to lower triglyceride accumulations and increase glucose uptake.57 In the liver, adiponectin improves insulin sensitivity while reducing triglyceride content and gluconeogenesis.57–60 Cats are animals that eat diets plentiful in protein and low in carbohydrates; thus, they rely on gluconeogenesis from amino acids to maintain blood glucose concentrations. Dietary protein is a potent stimulator of insulin release in cats. Although most animals suppress gluconeogenesis during meals, cats actually increase hepatic glucose production during the absorptive phase to offset increased amounts of insulin.61,62 Because cats maintain a gluconeogenic state longer than that of other species, the impact of adiponectin on liver glucose production is unknown. Adiponectin does not appear to affect glucose uptake, glycogen synthesis, or glycogenolysis in the liver in humans or rodents.57
Studies focusing on adiponectin in cats are extremely limited in number. Similar to results for other species, adiponectin mRNA expression in cats has been detected only in adipose tissue.63,64,a Adiponectin concentrations also correlate inversely with body mass in cats.24,63 Results from our laboratory groupa are in concert with those of another study64 and suggest that cats differ from other species in their pattern of adiponectin mRNA expression. Humans secrete 25% to 60% less adiponectin from visceral tissues, compared with secretion from subcutaneous adipose tissues, whereas cats express 12% to 50% more adiponectin mRNA from visceral depots.64–67 Similar to the results for leptin, adiponectin concentrations were not altered in a study24 in which effects of high carbohydrate–low protein and low carbohydrate–high protein diets were compared. This is in agreement with results of a study68 in humans in which investigators found no difference in adiponectin concentrations between subjects consuming low fat–high carbohydrate and low fat–high protein diets.
Indirect evidence regarding the function of adiponectin in cats can be derived from experiments conducted to evaluate the use of an insulin-sensitizer that is in the TZD class of drugs. In humans, TZDs (also known as glitazones) indirectly increase secretion of adiponectin.69 In 1 study,70 darglitazone treatment of obese cats lowered cholesterol, triglyceride, and leptin concentrations, compared with results for placebo-treated cats.70 There was also a significant decrease in the area under the curve for nonesterified fatty acids, glucose, and insulin during IV glucose tolerance testing.70 These results are consistent with those seen after TZD administration in humans and may indicate that adiponectin has similar effects in these 2 species. Further evaluation of TZD medications and adiponectin in cats is warranted and may provide new treatment options for cats with diabetes mellitus.
Conclusions
As more is learned about the role of adipose tissue as an endocrine organ, it becomes clear that maintaining proper body fat mass is critical for good health. The deleterious effects of excessive amounts of adipose tissue have been implicated in the cause or progression of urogenital diseases, endocrinopathies, metabolic derangements, dermatologic diseases, and orthopedic disorders in cats.71–73 Many of these pathologic conditions may be related to the secretion of adipokines from adipose tissue. The information provided here has focused primarily on results of studies conducted in humans. Because cats are a metabolically unique species, results from studies in rodents and humans may not be applicable. It is hoped that this information will prompt additional research that focuses on the impact of adipokines in veterinary species. By understanding the physiologic roles of hormones and cytokines such as leptin, TNF-α, and adiponectin, clinicians should enhance their ability to combat obesity-associated diseases and improve the health of feline patients.
ABBREVIATIONS
| HMW | High molecular weight |
| TNF | Tumor necrosis factor |
| TZD | Thiazolidinedione |
Lusby A, Kania S, Bartges J, et al. Adiponectin mRNA expression in the cat (abstr), in Proceedings. Nestlé Purina Nutr Forum, 2008;70.
References
- 1.
Anderson R. Obesity in the dog and cat. Vet Annu 1974;1441:182–186.
- 2.↑
Lund EM, Armstrong PJ, Kirk CA, et al. Prevalence and risk factors for obesity in adult cats from private US veterinary practices. Int J Appl Res Vet Med 2005;3:88–96.
- 3.↑
Prahl A, Guptill L, Glickman NW, et al. Time trends and risk factors for diabetes mellitus in cats presented to veterinary teaching hospitals. J Feline Med Surg 2007;9:351–358.
- 4.↑
Halberg N, Wernstedt-Asterholm I, Scherer PE. The adipocyte as an endocrine cell. Endocrinol Metab Clin North Am 2008;37:753–768.
- 5.↑
Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995;269:543–546.
- 6.↑
Zhang F, Chen Y, Heiman M, et al. Leptin: structure, function and biology. In: Litwack G, ed. Vitamins and hormones. Vol 71. San Diego: Academic Press Inc, 2005;345–372.
- 7.↑
Munzberg H, Myers MG Jr. Molecular and anatomical determinants of central leptin resistance. Nat Neurosci 2005;8:566–570.
- 8.
Oswal A, Yeo GSH. The leptin melanocortin pathway and the control of body weight: lessons from human and murine genetics. Obes Rev 2007;8:293–306.
- 9.
Horvath TL. Synaptic plasticity in energy balance regulation. Obesity (Silver Spring) 2006;14:228S–233S.
- 10.↑
Anukulkitch C, Rao A, Dunshea F, et al. A test of the lipostat theory in a seasonal (ovine) model under natural conditions reveals a close relationship between adiposity and melanin concentrating hormone expression. Domest Anim Endocrinol 2009;36:138–151.
- 11.↑
Münzberg H, Björnholm M, Bates SH, et al. Leptin receptor action and mechanisms of leptin resistance. Cell Mol Life Sci 2005;62:642–652.
- 13.↑
Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999;282:1568–1575.
- 14.↑
Appleton DJ, Rand JS, Sunvold GD. Plasma leptin concentrations in cats: reference range, effect of weight gain and relationship with adiposity as measured by dual energy x-ray absorptiometry. J Feline Med Surg 2000;2:191–199.
- 15.↑
Backus RC, Havel PJ, Gingerich RL, et al. Relationship between serum leptin immunoreactivity and body fat mass as estimated by use of a novel gas-phase Fourier transform infrared spectroscopy deuterium dilution method in cats. Am J Vet Res 2000;61:796–801.
- 16.↑
Park S, Hong SM, Sung SR, et al. Long-term effects of central leptin and resistin on body weight, insulin resistance, and B-cell function and mass by the modulation of hypothalamic leptin and insulin signaling. Endocrinology 2008;149:445–454.
- 17.
Griffin ME, Marcucci MJ, Cline GW, et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 1999;48:1270–1274.
- 18.
Boden G. Effects of free fatty acids (FFA) on glucose metabolism: significance for insulin resistance and type 2 diabetes. Exp Clin Endocrinol Diabetes 2003;111:121–124.
- 19.↑
Dyck DJ, Heigenhauser GJF, Bruce CR. The role of adipokines as regulators of skeletal muscle fatty acid metabolism and insulin sensitivity. Acta Physiol 2006;186:5–16.
- 20.↑
Sell H, Dietze-Schroeder D, Eckel J. The adipocyte-myocyte axis in insulin resistance. Trends Endocrinol Metab 2006;17:416–422.
- 21.↑
Benomar Y, Wetzler S, Larue-Achagiotis C, et al. In vivo leptin infusion impairs insulin and leptin signalling in liver and hypothalamus. Mol Cell Endocrinol 2005;242:59–66.
- 22.↑
Ceddia RB, Koistinen HA, Zierath JR, et al. Analysis of paradoxical observations on the association between leptin and insulin resistance. FASEB J 2002;16:1163–1176.
- 23.↑
Martin LJM, Siliart B, Dumon HJW, et al. Spontaneous hormonal variations in male cats following gonadectomy. J Feline Med Surg 2006;8:309–314.
- 24.↑
Hoenig M, Thomaseth K, Waldron M, et al. Insulin sensitivity, fat distribution, and adipocytokine response to different diets in lean and obese cats before and after weight loss. Am J Physiol Regul Integr Comp Physiol 2007;292:R227–R234.
- 25.↑
Appleton DJ, Rand JS, Sunvold GD. Plasma leptin concentrations are independently associated with insulin sensitivity in lean and overweight cats. J Feline Med Surg 2002;4:83–93.
- 26.↑
Backus RC, Cave NJ, Keisler DH. Gonadectomy and high dietary fat but not high dietary carbohydrate induce gains in body weight and fat of domestic cats. Br J Nutr 2007;98:641–650.
- 27.↑
Belsito KR, Vester BM, Keel T, et al. Impact of ovariohysterectomy and food intake on body composition, physical activity, and adipose gene expression in cats. J Anim Sci 2009;87:594–602.
- 28.↑
Kanchuk ML, Backus RC, Calvert CC, et al. Neutering induces changes in food intake, body weight, plasma insulin and leptin concentrations in normal and lipoprotein lipase-deficient male cats. J Nutr 2002;132:1730S–1732S.
- 29.↑
Hoenig M, Ferguson DC. Effects of neutering on hormonal concentrations and energy requirements in male and female cats. Am J Vet Res 2002;63:634–639.
- 30.
Coenen KR, Gruen ML, Chait A, et al. Diet-induced increases in adiposity, but not plasma lipids, promote macrophage infiltration into white adipose tissue. Diabetes 2007;56:564–573.
- 31.
Weisberg SP, McCann D, Desai M, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796–1808.
- 32.
Cinti S, Mitchell G, Barbatelli G, et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 2005;46:2347–2355.
- 34.↑
Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993;259:87–91.
- 35.↑
Ryden M, Arner P. Tumour necrosis factor-alpha in human adipose tissue—from signalling mechanisms to clinical implications. J Intern Med 2007;262:431–438.
- 36.
Mohamed-Ali V, Goodrick S, Rawesh A, et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab 1997;82:4196–4200.
- 37.↑
Miller C, Bartges J, Cornelius L, et al. Tumor necrosis factor-alpha levels in adipose tissue of lean and obese cats. J Nutr 1998;128:2751S–2752S.
- 38.↑
Hoenig M, McGoldrick JB, deBeer M, et al. Activity and tissue-specific expression of lipases and tumor-necrosis factor alpha in lean and obese cats. Domest Anim Endocrinol 2006;30:333–344.
- 39.↑
Peraldi P, Xu M, Spiegelman BM. Thiazolidinediones block tumor necrosis factor-alpha induced inhibition of insulin signaling. J Clin Invest 1997;100:1863–1869.
- 41.
Kim KY, Kim JK, Jeon JH, et al. c-Jun N-terminal kinase is involved in the suppression of adiponectin expression by TNF-alpha in 3T3–L1 adipocytes. Biochem Biophys Res Commun 2005;327:460–467.
- 42.
Kita A, Yamasaki H, Kuwahara H, et al. Identification of the promoter region required for human adiponectin gene transcription: association with CCAAT/enhancer binding protein-beta and tumor necrosis factor-alpha. Biochem Biophys Res Commun 2005;331:484–490.
- 43.↑
Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999;257:79–83.
- 44.↑
Swarbrick MM, Havel PJ. Physiological, pharmacological, and nutritional regulation of circulating adiponectin concentrations in humans. Metab Syndr Relat Disord 2008;6:87–102.
- 45.
Iwaki M, Matsuda M, Maeda N, et al. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 2003;52:1655–1663.
- 46.
Waki H, Yamauchi T, Kamon J, et al. Generation of globular fragment of adiponectin by leukocyte elastase secreted by monocytic cell line THP-1. Endocrinology 2005;146:790–796.
- 47.
Pajvani UB, Hawkins M, Combs TP, et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem 2004;279:12152–12162.
- 48.
Fisher FF, Trujillo ME, Hanif W, et al. Serum high molecular weight complex of adiponectin correlates better with glucose tolerance than total serum adiponectin in Indo-Asian males. Diabetologia 2005;48:1084–1087.
- 49.↑
Matsuzawa Y. Adiponectin: identification, physiology and clinical relevance in metabolic and vascular disease. Atheroscler Suppl 2005;6:7–14.
- 50.
Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001;86:1930–1935.
- 51.
Kantartzis K, Fritsche A, Tschritter O, et al. The association between plasma adiponectin and insulin sensitivity in humans depends on obesity. Obes Res 2005;13:1683–1691.
- 52.
Tschritter O, Fritsche A, Thamer C, et al. Plasma adiponectin concentrations predict insulin sensitivity of both glucose and lipid metabolism. Diabetes 2003;52:239–243.
- 53.↑
Hotta K, Funahashi T, Bodkin NL, et al. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 2001;50:1126–1133.
- 54.
Lindsay RS, Funahashi T, Hanson RL, et al. Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet 2002;360:57–58.
- 55.
Yamamoto Y, Hirose H, Saito I, et al. Adiponectin, an adipocyte-derived protein, predicts future insulin resistance: two-year follow-up study in Japanese population. J Clin Endocrinol Metab 2004;89:87–90.
- 56.
Snehalatha C, Mukesh B, Simon M, et al. Plasma adiponectin is an independent predictor of type 2 diabetes in Asian Indians. Diabetes Care 2003;26:3226–3229.
- 57.↑
Karbowska J, Kockan Z. Role of adiponectin in the regulation of carbohydrate and lipid metabolism. J Physiol Pharmacol 2006;57:103–113.
- 58.
Berg AH, Combs TP, Du X, et al. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001;7:947–953.
- 59.
Combs TP, Berg AH, Obici S, et al. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest 2001;108:1875–1881.
- 60.
Deepa SS, Dong LQ. APPL1: role in adiponectin signaling and beyond. Am J Physiol Endocrinol Metab 2009;296:E22–E36.
- 61.
Rogers QR, Morris JG, Freedland RA. Lack of hepatic enzymatic adaptation to low and high levels of dietary protein in the adult cat. Enzyme 1977;22:348–356.
- 62.
Zoran DL. The carnivore connection to nutrition in cats. J Am Vet Med Assoc 2002;221:1559–1567.
- 63.
Ishioka K, Omachi A, Sasaki N, et al. Feline adiponectin: molecular structures and plasma concentrations in obese cats. J Vet Med Sci 2009;71:189–194.
- 64.↑
Zini E, Linscheid P, Franchini M, et al. Partial sequencing and expression of genes involved in glucose metabolism in adipose tissues and skeletal muscle of healthy cats. Vet J 2009;180:66–70.
- 65.
Hernandez-Morante JJ, Milagro FI, Larque E, et al. Relationship among adiponectin, adiponectin gene expression and fatty acids composition in morbidly obese patients. Obes Surg 2007;17:516–524.
- 66.
Lihn AS, Bruun JM, He G, et al. Lower expression of adiponectin mRNA in visceral adipose tissue in lean and obese subjects. Mol Cell Endocrinol 2004;219:9–15.
- 67.
Fisher FM, McTernan PG, Valsamakis G, et al. Differences in adiponectin protein expression: effect of fat depots and type 2 diabetic status. Horm Metab Res 2002;34:650–654.
- 68.↑
Claessens M, van Baak MA, Monsheimer S, et al. The effect of a low-fat, high-protein or high-carbohydrate ad libitum diet on weight loss maintenance and metabolic risk factors. Int J Obes 2009;33:296–304.
- 69.↑
Riera-Guardia N, Rothenbacher D. The effect of thiazolidinediones on adiponectin serum level: a meta-analysis. Diabetes Obes Metab 2008;10:367–375.
- 70.↑
Hoenig M, Ferguson DC. Effect of darglitazone on glucose clearance and lipid metabolism in obese cats. Am J Vet Res 2003;64:1409–1413.
- 71.
Lusby A, Kirk C. Obesity. In: Bonagura J, Twedt DC, eds. Kirk's current veterinary therapy XIV. Philadelphia: Saunders, 2008;191–195.
- 72.
Scarlett JM, Donoghue S. Associations between body condition and disease in cats. J Am Vet Med Assoc 1998;212:1725–1731.
- 73.
Buffington CA. External and internal influences on disease risk in cats. J Am Vet Med Assoc 2002;220:994–1002.
