Inhibition of high-fat diet-induced inflammatory responses in adipose tissue by SF1-expressing neurons of the ventromedial hypothalamus.

Inflammation and thermogenesis in white adipose tissue (WAT) at different sites influence the overall effects of obesity on metabolic health. In mice fed a high-fat diet (HFD), inflammatory responses are less pronounced in inguinal WAT (ingWAT) than in epididymal WAT (epiWAT). Here we show that ablation and activation of steroidogenic factor 1 (SF1)-expressing neurons in the ventromedial hypothalamus (VMH) oppositely affect the expression of inflammation-related genes and the formation of crown-like structures by infiltrating macrophages in ingWAT, but not in epiWAT, of HFD-fed mice, with these effects being mediated by sympathetic nerves innervating ingWAT. In contrast, SF1 neurons of the VMH preferentially regulated the expression of thermogenesis-related genes in interscapular brown adipose tissue (BAT) of HFD-fed mice. These results suggest that SF1 neurons of the VMH differentially regulate inflammatory responses and thermogenesis among various adipose tissue depots and restrain inflammation associated with diet-induced obesity specifically in ingWAT.

Homeostatic versus hedonic control of carbohydrate selection.

Macronutrient intake is associated with cardiometabolic health, ageing and longevity, but the mechanisms underlying its regulation have remained unclear. Most rodents increase carbohydrate selection under certain physiological and pathological conditions such as fasting. When presented with a choice between a basally preferable high-fat diet (HFD) and a high-carbohydrate diet (HCD) such as a high-sucrose diet, fasted mice first eat the HFD and then switch to the HCD during the first few hours of refeeding and continue to eat the HCD up to 24 h in the two-diet choice approach. Such consumption of an HCD after fasting reverses the fasting-induced increase in the plasma concentration of ketone bodies more rapidly than does refeeding with an HFD alone. 5'-AMP-activated protein kinase (AMPK)-regulated neurons in the paraventricular nucleus of the hypothalamus (PVH) that express corticotropin-releasing hormone (CRH) are necessary and sufficient for the fasting-induced selection of carbohydrate over an HFD in mice. These neurons appear to contribute to a fasting-induced increase in the positive valence of carbohydrate without affecting the preference for more palatable and energy-dense diets such as an HFD. Identification of the neural circuits in which AMPK-regulated CRH neurons in the PVH of mice are embedded should shed new light on the physiological and molecular mechanisms responsible for macronutrient selection.

Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake.

Agouti-related peptide (AgRP) neurons of the hypothalamus play a key role in regulating food intake and body weight, by releasing three different orexigenic molecules: AgRP; GABA; and neuropeptide Y. AgRP neurons express various G protein-coupled receptors (GPCRs) with different coupling properties, including Gs-linked GPCRs. At present, the potential role of Gs-coupled GPCRs in regulating the activity of AgRP neurons remains unknown. Here we show that the activation of Gs-coupled receptors expressed by AgRP neurons leads to a robust and sustained increase in food intake. We also provide detailed mechanistic data linking the stimulation of this class of receptors to the observed feeding phenotype. Moreover, we show that this pathway is clearly distinct from other GPCR signalling cascades that are operative in AgRP neurons. Our data suggest that drugs able to inhibit this signalling pathway may become useful for the treatment of obesity.