Acute disruption of leptin signaling in vivo leads to increased insulin levels and insulin resistance.

Leptin, an adipocyte-derived hormone, plays an essential role in the maintenance of normal body weight and energy expenditure, as well as glucose homeostasis. Indeed, leptin-deficient ob/ob mice are obese with profound hyperinsulinemia, insulin resistance, and often hyperglycemia. Interestingly, low doses of exogenous leptin can reverse the hyperinsulinemia and hyperglycemia in these animals without altering body weight. The hyperinsulinemia in ob/ob mice may result directly from the absence of leptin signaling in pancreatic ß-cells and, in turn, contribute to both obesity and insulin resistance. Here, we acutely attenuated endogenous leptin signaling in normal mice with a polyethylene glycol (PEG)ylated mouse leptin antagonist (PEG-MLA) to determine the contribution of leptin signaling in the regulation of glucose homeostasis. PEG-MLA was either injected or continuously administered via osmotic minipumps for several days, and various metabolic parameters were assessed. PEG-MLA-treated mice had increased fasting and glucose-stimulated plasma insulin levels, decreased whole-body insulin sensitivity, elevated hepatic glucose production, and impaired insulin-mediated suppression of hepatic glucose production. Moreover, PEG-MLA treatment resulted in increased food intake and increased respiratory quotient without significantly altering energy expenditure or body composition as assessed by the lean:lipid ratio. Our findings indicate that alterations in insulin sensitivity occur before changes in the lean:lipid ratio and energy expenditure during the acute disruption of endogenous leptin signaling.

Ldlr-/- mice display decreased susceptibility to Western-type diet-induced obesity due to increased thermogenesis.

The low-density lipoprotein receptor (Ldlr) is a key molecule involved with lipid clearance. The Ldlr(-/-) mouse has been used extensively as a model for studying atherosclerosis. This study sought to characterize the energy balance phenotype of Ldlr(-/-) mice with respect to weight gain, body composition, energy expenditure (EE), glucose homeostasis, and leptin sensitivity. Adult Ldlr(-/-) mice and Ldlr(+/+) controls on a C57Bl/6J background were fed either a chow or a high-fat, high-sucrose Western-type diet (WTD) for eight wk. Physiological studies of food intake, EE, activity, insulin sensitivity, and leptin responsiveness were performed. The effect of these diet interventions on circulating leptin and on leptin gene expression was also examined. On the chow diet, Ldlr(-/-) mice had lower EE and higher activity levels relative to controls. On the WTD, Ldlr(-/-) mice gained less weight relative to Ldlr(+/+) mice, specifically gaining less fat mass. Increased thermogenesis in Ldlr(-/-) mice fed the WTD was detected. Additionally, leptin responsiveness was blunted in chow-fed Ldlr(-/-) mice, suggesting a novel role for the Ldlr pathway that extends to leptin's regulation of energy balance. In addition to its known role in lipid transport, these results demonstrate the importance of the Ldlr in energy homeostasis and suggest a direct physiological link between altered lipid transport and energy balance.

The metabolic phenotype of SCD1-deficient mice is independent of melanin-concentrating hormone.

We propose that deletion of pro-melanin-concentrating hormone (pMCH) would increase energy expenditure and further improve glucose tolerance in mice lacking stearoyl-coA desaturase-1 (SCD1). To test our hypothesis, we bred and metabolically challenged Pmch-/-; Scd1-/- double-knockout mice, with comparison to Pmch-/- mice; Scd1-/- mice and C57Bl/6J controls. Deletion of both Pmch and Scd1 increased both food intake and energy expenditure relative to control mice. Pmch-/-; Scd1-/- double-knockout mice had improved glucose tolerance relative to control mice. The majority of the metabolic effects were contributed by inactivation of the Scd1 gene. We conclude that the increased food intake and increased energy expenditure of Scd1-/- mice are independent of the neuropeptide melanin-concentrating hormone.

Effects of glucose and insulin on acyl ghrelin and desacyl ghrelin, leptin, and adiponectin in pregnant women with diabetes.

The aim of the study was to compare the regulation of ghrelin, leptin, and adiponectin by insulin and glucose during the second and third trimesters of pregnancy in women with diabetes. We studied 9 pregnant women with diabetes. All women were treated with insulin and omitted the morning dose on the day of the test. After collection of baseline fasting samples, we performed 3 successive glucose clamps: 2 euglycemic clamps (glucose, 5 mmol/L; insulin infusion at 20 and 40 mU m(-2) min(-1)) and 1 hyperglycemic clamp (glucose, 10 mmol/L; insulin infusion at 40 mU m(-2) min(-1)). We determined concentrations of acyl and desacyl ghrelin (using a double-antibody sandwich assay that recognizes the full-length molecule), leptin, and adiponectin. Fasting desacyl ghrelin concentrations decreased, whereas insulin and leptin concentrations increased, between the second and third trimesters of pregnancy (P < or = .011). During the clamp studies, desacyl ghrelin concentrations decreased by 33% (second trimester, P = .004) and 27% (third trimester, P = .09) with increasing glucose and insulin concentrations, whereas acyl ghrelin, leptin, and adiponectin concentrations were unaffected. Glucose and insulin regulate desacyl ghrelin concentrations in pregnant women with diabetes. Impaired desacyl ghrelin regulation may affect energy metabolism in pregnant women with poorly controlled diabetes.