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The endocannabinoid system plays a critical role in the control of energy homeostasis, but the identity and localization of the endocannabinoid signal involved remain unknown. In the present study, we developed transgenic mice that overexpress in forebrain neurons the presynaptic hydrolase, monoacylglycerol lipase (MGL), which deactivates the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). MGL-overexpressing mice show a 50% decrease in forebrain 2-AG levels but no overt compensation in other endocannabinoid components. This biochemical abnormality is accompanied by a series of metabolic changes that include leanness, elevated energy cost of activity, and hypersensitivity to β(3)-adrenergic-stimulated thermogenesis, which is corrected by reinstating 2-AG activity at CB(1)-cannabinoid receptors. Additionally, the mutant mice are resistant to diet-induced obesity and express high levels of thermogenic proteins, such as uncoupling protein 1, in their brown adipose tissue. The results suggest that 2-AG signaling through CB(1) regulates the activity of forebrain neural circuits involved in the control of energy dissipation.

Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (C[B.sub.1]R) is critical for the central regulation of food intake. Here we test whether C[B.sub.1]R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of C[B.sub.1]R activity increases feeding, and notably, C[B.sub.1]R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for C[B.sub.1]R -induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances C[B.sub.1]R-driven feeding. The Pomc gene encodes both the anorexigenic peptide a-melanocyte-stimulating hormone, and the opioid peptide β-endorphin. C[B.sub.1]R activation selectively increases β-endorphin but not α- melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute C[B.sub.1]R -induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish C[B.sub.1]R -induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids., Feeding behaviour is under the control of hypothalamic circuits (1). In the hypothalamic arcuate nucleus (ARC), Agouti-related peptide (AgRP)expressing neurons, when activated, promote food intake (2,3), whereas POMC-producing neurons promote [...]

Activation of central PPARγ promotes food intake and body weight gain; however, the identity of the neurons that express PPARγ and mediate the effect of this nuclear receptor on energy homeostasis is unknown. Here, we determined that selective ablation of PPARγ in murine proopiomelanocortin (POMC) neurons decreases peroxisome density, elevates reactive oxygen species, and induces leptin sensitivity in these neurons. Furthermore, ablation of PPARγ in POMC neurons preserved the interaction between mitochondria and the endoplasmic reticulum, which is dysregulated by HFD. Compared with control animals, mice lacking PPARγ in POMC neurons had increased energy expenditure and locomotor activity; reduced body weight, fat mass, and food intake; and improved glucose metabolism when exposed to high-fat diet (HFD). Finally, peripheral administration of either a PPARγ activator or inhibitor failed to affect food intake of mice with POMC-specific PPARγ ablation. Taken together, our data indicate that PPARγ mediates cellular, biological, and functional adaptations of POMC neurons to HFD, thereby regulating whole- body energy balance., Introduction Pharmacological compounds that activate PPARs, such as thiazolidinediones, have been used as highly effective oral medications for type 2 diabetes due to their ability to increase systemic insulin sensitivity. [...]

Previous studies have proposed roles for hypothalamic reactive oxygen species (ROS) in the modulation of circuit activity of the melanocortin system (1,2). Here we show that suppression of ROS diminishes [...]

The anorexigenic neuromodulator [alpha]-melanocyte--stimulating hormone ([alpha]-MSH; referred to here as [alpha]-[MSH.sub.1-13]) undergoes extensive posttranslational processing, and its in vivo activity is short lived due to rapid inactivation. The enzymatic control of [alpha]-[MSH.sub.1-13] maturation and inactivation is incompletely understood. Here we have provided insight into [alpha]-[MSH.sub.1-13] inactivation through the generation and analysis of a subcongenic mouse strain with reduced body fat compared with controls. Using positional cloning, we identified a maximum of 6 coding genes, including that encoding prolylcarboxypeptidase (PRCP), in the donor region. Real-time PCR revealed a marked genotype effect on Prcp mRNA expression in brain tissue. Biochemical studies using recombinant PRCP demonstrated that PRCP removes the C-terminal amino acid of [alpha]-[MSH.sub.1-13], producing [alpha]-[MSH.sub.1-12], which is not neuroactive. We found that Prcp was expressed in the hypothalamus in neuronal populations that send efferents to areas where [alpha]-[MSH.sub.1-13] is released from axon terminals. The inhibition of PRCP activity by small molecule protease inhibitors administered peripherally or centrally decreased food intake in both wild-type and obese mice. Furthermore, Prcp-null mice had elevated levels of [alpha]-[MSH.sub.1-13] in the hypothalamus and were leaner and shorter than the wild-type controls on a regular chow diet; they were also resistant to high-fat diet--induced obesity. Our results suggest that PRCP is an important component of mela-nocortin signaling and weight maintenance via control of active [alpha]-[MSH.sub.1-13] levels., Introduction Analysis of congenic mouse strains provides a general method to identify genes for complex traits using positional genetics tools. Congenic mouse strain analyses have successfully identified several positional candidate [...]

The gut-derived hormone ghrelin exerts its effect on the brain by regulating neuronal activity. Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein [...]

Author(s): Qian Gao (corresponding author) [1]; Gabor Mezei [1]; Yongzhan Nie [1]; Yan Rao [1]; Cheol Soo Choi [2]; Ingo Bechmann [3]; Csaba Leranth [1]; Dominique Toran-Allerand [4]; Catherine A [...]