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Peripheral insulin resistance and impaired insulin action are the primary characteristics of type 2 diabetes. The first observable defect in this major disorder occurs in muscle, where glucose disposal in response to insulin is impaired. We have developed a transgenic mouse with a dominant-negative insulin-like growth factor-I receptor (KR-IGF-IR) specifically targeted to the skeletal muscle. Expression of KR-IGF-IR resulted in the formation of hybrid receptors between the mutant and the endogenous IGF-I and insulin receptors, thereby abrogating the normal function of these receptors and leading to insulin resistance. Pancreatic ␤-cell dysfunction developed at a relative early age, resulting in diabetes. These mice provide an excellent model to study the molecular mechanisms underlying the development of human type 2 diabetes.

We tested the effect of chronic leptin treatment on fasting-induced torpor in leptin-deficient A-ZIP͞F-1 and ob͞ob mice. A-ZIP͞F-1 mice have virtually no white adipose tissue and low leptin levels, whereas ob͞ob mice have an abundance of fat but no leptin. These two models allowed us to examine the roles of adipose tissue and leptin in the regulation of entry into torpor. Torpor is a short-term hibernation-like state that allows conservation of metabolic fuels. We first characterized the A-ZIP͞F-1 animals, which have a 10-fold reduction in total body triglyceride stores. Upon fasting, A-ZIP͞F-1 mice develop a lower metabolic rate and decreased plasma glucose, insulin, and triglyceride levels, with no increase in free fatty acids or ␤-hydroxybutyrate. Unlike control mice, by 24 hr of fasting, they have nearly exhausted their triglycerides and are catabolizing protein. To conserve energy supplies during fasting, A-ZIP͞F-1 (but not control) mice entered deep torpor, with a minimum core body temperature of 24°C, 2°C above ambient. In ob͞ob mice, fasting-induced torpor was completely reversed by leptin treatment. In contrast, neither leptin nor thyroid hormone prevented torpor in A-ZIP͞F-1 mice. These data suggest that there are at least two signals for entry into torpor in mice, a low leptin level and another signal that is independent of leptin and thyroid hormone levels. Studying rodent torpor provides insight into human torpor-like states such as near drowning in cold water and induced hypothermia for surgery.fasting ͉ lipoatrophic diabetes ͉ body temperature ͉ hypothermia ͉ A-ZIP͞F-1 mice L iving organisms must cope with food scarcity. The capabilities to store excess fuel and regulate energy expenditure were thus crucial evolutionary adaptations. In higher organisms, white adipocytes store triglycerides that are burned during fasting and starvation (1, 2). These adipocyte triglycerides account for the vast majority of the body's fuel reserves (3).Adipose tissues also contribute to energy homeostasis in an endocrine͞paracrine manner. Leptin is secreted by adipocytes in direct proportion to body fat mass and regulates energy expenditure, metabolic efficiency, and food intake (4-6). Leptin binds to receptors in the hypothalamus and other sites and conveys the size of adipose tissue lipid stores. Adipocytes also make additional hormones, including tumor necrosis factor ␣, which affects insulin sensitivity (7,8). Thus it is clear that adipose tissues contribute to energy metabolism in two ways, as a metabolic regulator and fuel depot.To analyze the physiologic roles of fat, we generated a transgenic mouse, named A-ZIP͞F-1, which has virtually no white adipose tissue and a reduced amount of brown adipose tissue (9). These mice express, selectively in adipose tissue, a dominant negative protein that heterodimerizes with certain basic leucine zipper transcription factors. The A-ZIP͞F-1 phenotype strikingly resembles that of humans with severe lipoatrophic diabetes mellitus, a disease characterized by reduced amounts of...