Felipedia

Obesity in Cats

Obesity is an excessively high amount of body fat or adipose tissue in relation to lean body mass. The incidence of obesity is increasing at a rapid rate in human beings and in pets. It is now considered the most common nutritional disorder of cats and dogs. Obesity in cats concerns veterinarians because it increases the risk of other diseases, in particular, diabetes mellitus, dermatopathies, fatty liver syndrome and lameness.

Although many aspects of obesity are similar among species, numerous differences also exist. For example, obesity in people frequently is associated with dyslipidemia. Development of cardiovascular disease and hypertension has been attributed primarily to an increase in low density lipoprotein (LDL), the sow-called 'bad' cholesterol, and a decrease in high density lipoprotein (HDL), the so-called 'good' cholesterol. In comparison, cats have elevated HDL concentrations when they become obese, probably because of lack of cholesterol-ester-transfer protein (CETP), an enzyme involved in the transfer of cholesterol and lipids between different lipoproteins. Interestingly, this enzyme recently has been targeted to treat dyslipidemia in people; that is, inhibition of CETP leads to increased HDL and decreased LDL concentrations.

Pathogenesis

Changes in both insulin secretion and action play a primary role in the pathogenesis of obesity and diabetes mellitus.

1. Insulin secretion

Insulin secretion (see Drugs list for doses) has been evaluated in cats primarily with the intravenous glucose tolerance test (IVGTT), although this test measures insulin action and secretion. Glucose is the major stimulus for insulin secretion in cats as in many other species. Other substances such as amino acids also cause insulin release but only in the presence of glucose. During an IVGTT, the response to an IV bolus of glucose is measured over a 2 hr time period. In healthy lean cats, glucose leads to a biphasic release of insulin, which is characterised by an acute or first phase and a second or maintenance phase. Serum glucose and insulin concentrations return to baseline concentrations at 3 hrs.

When cats become obese, the secretion pattern seen in an IVGTT changes and is characterised by a decrease in the area under the curve (AUC) of the acute or first phase but an increase in AUC of the second or maintenance phase. Other species have demonstrated that the rapid, acute phase is necessary for the inhibition of glucose output by the liver; therefore in obese animals with a diminished acute phase, hepatic glucose output rises. the increase in the second phase is likely due to peripheral (tissue) factors that cause insulin resistance and a response to the increase in endogenous glucose concentrations.

Changes in insulin secretion on an IVGTT actually may precede obesity as well. In a group of lean cats from a varied genetic background housed identically and fed ad libitum, all cats became obese but only a proportion became glucose intolerant. Interestingly, those that became glucose intolerant had an increased second-phase insulin secretion even when still lean, which suggests that the action of insulin decreased and that peripheral insulin resistance may precede a defect in insulin secretion.

A highly specific marker of changes in insulin secretion and predictor for progression to diabetes mellitus in human beings is the insulin / proinsulin ratio. Normally, insulin is made as a precursor molecule, proinsulin, which is then processed; that is, part of the amino chain is cleaved, making the mature molecule, insulin. With increasing demand for insulin secretion in obese subjects, the cleavage or proinsulin to insulin becomes inefficient, more proinsulin is secreted, and the ratio decreases. However, because of lack of a feline assay specific for proinsulin versus insulin, whether this phenomenon occurs in cats has not been examined,

2. Insulin resistance

Obesity is characterised in many species by insulin resistance, which is defined as the inability of insulin to promote glucose uptake and to suppress hepatic insulin output. Insulin resistance is present in obese cats as has been shown recently in experiments with the use of the gold standard testing method, the euglycaemic hyperinsulinaemic clamp. Obese cats showed an approximately 50% decrease in insulin sensitivity compared with lean cats, possibly because, at least in part, of changes in glucose transporters. In many tissues, including muscle and fat, insulin facilitates glucose entry by increasing translocation of glucose transporters to the cell membrane. GLUT4 is the major insulin-sensitive glucose transporter found in muscle and fat, whereas GLUT1 is insulin independent and found in most tissues throughout the body. In muscle and fat from obese cats compared with lean cats, GLUT4 expression is decreased several-fold, whereas GLUT1 expression is unchanged. These changes occurred early in the development of obesity when fasting glucose concentration or glycosylated haemoglobin concentrations were not different between the two groups, which suggests that factors other than glucose are causing initial changes in insulin action.

Changes in fat metabolism may alter the actions of insulin. In human beings and other species, obesity leads to an increase in non-esterified fatty acids (NEFAs), which are thought to cause insulin resistance. Obese cats similarly have elevated NEFA concentrations, with higher levels in obese males than females. Myocellular lipid deposition also may lead to insulin resistance. In rodents, human beings and cats, the triglyceride content of muscle correlates negatively with whole body insulin sensitivity, and obese cats have an increase in muscle lipid content as measured by magnetic resonance imaging. In lean subjects, fatty acids are oxidized in muscle; however, with obesity, oxidation decreases and re-esterification increases. The result is lipid deposition, which is thought to interfere with glucose uptake and metabolism.

The response of obese cats to the thiazolidinedione drug glitazone supports the notion that lipid oxidation is abnormal and causes changes in glucose metabolism. Treatment of obese cats with darglitazone led to increased insulin sensitivity. Part of the physiological action of this classification of drugs is related to their ability to bind to and activate nuclear peroxisome proliferator activating receptor gamma (PPARG). PPARG is expressed in several tissues and is required for adipogenesis. One the one hand, thiazolidinediones increase lipogenesis but through stimulation of expression of mitochondrial uncoupling proteins 2 and 3, they also increase fatty acid oxidation and enhance thermogenesis and energy dissipation. As a result, intracellular lipid is redistributed from insulin-responsive organs such as muscle into peripheral adipocytes, thereby increasing insulin sensitivity.

Increased lipids are involved in decreasing glucose transport and in increasing hepatic glucose production. Initially, pancreatic beta cells increase insulin secretion to compensate for two changes that occur in obesity; increased endogenous glucose production and decreased clearance. As a result, blood glucose concentrations remain in the normal range. However, with time, beta-cell function declines and blood glucose concentrations increase, a phenomenon referred to as 'exhaustion', which likely is due to a combination of changes in lipid and glucose metabolism (glucotoxicity and lipotoxicity), among others.

A change in amylin secretion may contribute to the decline in beta-cell function. Amylin is a protein co-secreted with insulin that serves as the precursor molecule for the type of amyloid that forms in the pancreatic islets of most diabetic cats. In dogs with insulinomas and in cats treated with the sulfonylurea glipizide, continued stimulation of insulin secretion leads to amyloid deposition. which suggests that any long-term stimulation of insulin secretion, such as obesity, potentially could cause islet amyloid formation. Although amylin and insulin secretion increased together in cats made insulin-resistant, it is unclear what role amyloid plays in the pathogenesis of feline diabetes. Not all glucose-intolerant cats have pancreatic islet amyloid deposition, and the amount of amyloid deposited does not correlate highly with beta-cell functional defects. Unfortunately, the ability to perform controlled studies to evaluate the relation between amyloid deposition and insulin secretion is limited, because it is too invasive to evaluate cat pancreata histopathologically at different stages of insulin resistance and during the progression to diabetes. In addition, true loss in islet mass resulting from amyloid is difficult to quantify because pancreatic weight usually is not recorded at necropsy. However, recent evidence in transgenic mice suggests that amylin can form toxic molecules, which lead to beta-cell apoptosis, and beta-cell loss correlated positively with increasing glucose concentrations. Therefore amyloid deposition probably is not a cause of the initial defect in insulin secretion but may contribute to the progressive beta-cell failure in the majority of glucose-intolerant cats.

Many other hormones and cytokines are thought to be involved in the development of obesity and diabetes. Of those, leptin and adiponectin recently have received attention and have been examined in obese cats. Both are secreted from white adipose tissue, now considered an endocrine organ because it secretes cytokines and hormones, many of which influence glucose and lipid metabolism. Leptin is the product of the 'obesity gene' and modulates energy balance through central (satiety signal) and peripheral (energy expenditure) actions. The high leptin concentrations found in obesity are believed to be an indication of leptin resistance. Triglycerides recently have been implicated in the pathogenesis of leptin resistance, because they inhibit leptin transport into the brain, where it would act as a satiety signal. Leptin concentrations are increased in obese cats and decrease with weight loss, and therefore can be considered a marker of adipose mass.

Adiponectin expression and secretion are stimulated by PPARG, and serum concentration are correlated positively with insulin sensitivity. Adiponectin suppresses glucose production and inhibits inflammatory pathways and therefore plays an important role in the protection from atherosclerosis in human beings. Serum adiponectin concentrations are decreased in obesity and type 2 diabetes.

Progression to diabetes

The incidence of diabetes in cats clearly has increased in the last two decades, likely because of the increase in risk factors in general and obesity in particular. However, not all obese cats progress to become diabetic. Conversely, not all diabetic cats are obese at the time of diagnosis or ever have been. Not all diabetic cats have an increased amount of pancreatic amyloid deposition, and even cats with increased islet amyloid concentrations may have only transient diabetes. Last, not all diabetic cats respond to the same treatment. Many factors are therefore likely involved in the pathogenesis and clinical presentation of this disease.

Management of feline obesity

Management involves decreasing body weight and addressing the side effects of obesity until an ideal body weight is achieved. The evidence that obese cats have nearly three times the risk of death than cats of ideal weight helps to convince some owners.

Making weight loss happen involves 1) calorie restriction, 2) increasing physical activity. Calorie restriction is a more effective means in most cats due to the difficulty compared with dogs in increasing their physical activity.