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Reduced food intake brings about an adaptive decrease in energy expenditure that contributes to the recidivism of obesity after weight loss. Insulin and leptin inhibit food intake through actions in [...]

Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure. As their intracellular signaling converges at [...]

Insulin has pleiotropic biological effects in virtually all tissues. However, the relevance of insulin signaling in peripheral tissues has been studied far more extensively than its role in the brain. [...]

We present a consolidated view of the complexity and challenges of designing studies for measurement of energy metabolism in mouse models, including a practical guide to the assessment of energy expenditure, energy intake and body composition and statistical analysis thereof. We hope this guide will facilitate comparisons across studies and minimize spurious interpretations of data. We recommend that division of energy expenditure data by either body weight or lean body weight and that presentation of group effects as histograms should be replaced by plotting individual data and analyzing both group and body-composition effects using analysis of covariance (ANCOVA). [ABSTRACT FROM AUTHOR]

Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure. As their intracellular signaling converges at the PI3K pathway, we directly addressed the role of phosphatidylinositol3,4,5-trisphosphate-mediated (PIP3-mediated) signals in hypothalamic proopiomelanocortin (POMC) neurons by inactivating the gene for the PIP3 phosphatase Pten specifically in this cell type. Here we show that POMC-specific disruption of Pten resulted in hyperphagia and sexually dimorphic diet-sensitive obesity. Although leptin potently stimulated Stat3 phosphorylation in POMC neurons of POMC cell-restricted Pten knockout (PPKO) mice, it failed to significantly inhibit food intake in vivo. POMC neurons of PPKO mice showed a marked hyperpolarization and a reduction in basal firing rate due to increased ATP-sensitive potassium (KATP) channel activity. Leptin was not able to elicit electrical activity in PPKO POMC neurons, but application of the PI3K inhibitor LY294002 and the KATP blocker tolbutamide restored electrical activity and leptin-evoked firing of POMC neurons in these mice. Moreover, icv administration of tolbutamide abolished hyperphagia in PPKO mice. These data indicate that PIP3-mediated signals are critical regulators of the melanocortin system via modulation of KATP channels. [ABSTRACT FROM AUTHOR]

Insulin and leptin control food intake in part by regulating the transcription of orectic and anorectic neuropeptides in the hypothalamus. Activation of insulin receptor signaling results in nuclear exclusion of the transcription factor forkhead box-containing protein of the O subfamily (FoxO)-1, while Leptin activates the signal transducer and activator of transcription 3 (Stat3). We have previously shown that FoxO1 and Star3 exert opposing actions on the expression of Agrp and Pomc, resulting in activation of Agrp and inhibition of Pomc transcription. We reported that hypothalamic adenoviral delivery of constitutively nuclear FoxO1 blunted leptin's effect to acutely reduce food intake and body weight. However, it remains unclear whether chronic changes in hypothalamic FoxO1 activity affect the physiological regulation of energy homeostasis by insulin and leptin. To investigate the role of hypothalamic FoxO1 signaling in a genetic system, we inactivate the Foxol gene specifically in Pomc neurons in vivo, using cre/loxP technology in mice. Pomc-Foxo-/- mice were born at normal Mendelian ratios and had normal appearance at birth. Body weight in Pomc-specific Foxo1 knockout and wild type control animals was similar until 6-8 weeks of age, but subsequently both female and male mutant mice exhibited significantly reduced body weight compared to their wild type littermates. At 11 weeks, Pomc-Foxo-/- mice were significantly leaner (20.3±0.57 vs. 22.4±0.73 g in WT controls, P≤0.05). Importantly, reduced body weight in female mutant mice was accompanied by marked reduction of body fat content (7.0±1.05 vs. 3.7±0.43 %, P≤0.01 at wk. 14 in WT. vs. Pomc-Foxo-/females, respectively). While food intake under steady state conditions appeared unaltered, both female and male mice with Pomc-specific FoxOl-deficiency showed a blunted refeeding response to a 24h fast (88±5 vs. 73±4 mg/g/6h, P≤0.05; at wk.18, in WT. vs. Pomc-Foxo-/- males, respectively). These data are consistent with the hypothesis that FoxO1 is a critical player in hypothalamic Pomc neurons regulating energy homeostasis. Further physiologic analyses of Pomc-Foxo-/- mice are underway. ADA-Funded Research [ABSTRACT FROM AUTHOR]

In subgroups of a New Zealand obese mouse-derived backcross population with defined aberrations of glucose homeostasis, a comprehensive study of the hepatic expression of cytochrome P450 and glutathione S-transferase was performed. Three patterns of alterations in response to insulin resistance (normoglycemia/hyperinsulinemia) or diabetes (hyperglycemia/hypoinsulinemia) were observed: mRNA levels of Cyp2b9, Cyp3a16, Cyp4a14, and Gstt2 as assessed by Northern- and dot-blot analysis were increased markedly in liver from diabetic mice with no or only a slight increase in insulin resistant mice. Western-blot analysis detected the corresponding changes of the CYP2B and CYP4A proteins. In contrast, expression of Cyp2c22, Cyp2c29, and Cyp2c40 was reduced in diabetic, but normal in insulin resistant mice. These alterations were correlated with changes in serum free fatty acid levels and, therefore, seem to be mediated by the peroxisome proliferator activated receptor-alpha. Furthermore, expression of Cyp1a2, Cyp7b1, Gstm3, and Gstm6 was reduced in both diabetic and insulin resistant mice. Because this third pattern was not correlated with the alterations of serum free fatty acid levels, it seems to reflect an early alteration in the course of the disease, and may be related to the progression of the syndrome from insulin resistance to the type 2-like diabetes.