Overview of Defects in Thermogenesis in Rodent Models of Obesity

From the earliest studies of the obese mouse (now called leptin-deficient C57BL/6J Lepofe), there was evidence that these mice were not only obese, hyperglycemic, and hyperinsulinemic, but that they exhibited extreme sensitivity to the cold.10 Histologically, brown adipose tissue in these obese animals appears inactive in that it is infiltrated by white adipocytes and does not possess the rich density of mitochondria expressing UCP1 as normally seen in lean animals. The blunted capacity for adrenergic stimulation of lipolysis in adipose tissue of these animals (described below) probably also hinders the activation of UCP1 function by free fatty acids. Other monogenic obesity models and hypothalamic lesioning studies in rodents indicated a complex set of neural and endocrine abnormalities, culminating in the loss of homeo-static mechanisms controlling both food intake and metabolic efficiency.11

The suggestive role for brown fat and thermogenesis in body weight regulation was strengthened further by the generation of mice lacking brown fat as a consequence of targeted expression of diptheria toxin in brown adipo-cytes.12 These animals became obese and somewhat hyperphagic. Since the adipocyte-derived hormone leptin (the product of the ob locus13) regulates food intake, metabolic rate, and thermogenesis in brown fat,14-17 the obesity

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