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The rapid obesity surge in industrialized countries is attributed to genetic susceptibility and environmental factors; however, the primary defects that lead to obesity are still largely unknown. This Review summarizes our current knowledge about the neuronal populations and intracellular signaling molecules that are involved in maintaining normal body weight.

5-hydroxytryptamine 2C receptors (5-HT2CRs) in the brain have been shown to regulate glucose homeostasis. Xu and colleagues find that 5-HT2CRs expressed specifically by hypothalamic pro-opiomelanocortin neurons are involved in the regulation of insulin sensitivity and glucose homeostasis in liver.

A new optogenetics study finds that stimulation of pro-opiomelanocortin (POMC) and agouti-related peptide (AGRP) neurons acutely regulates feeding behavior. AGRP-induced hyperphagia is independent of melanocortin signaling.

Mice lacking Toll-like receptor 4 (Tlr4) do not develop diet-induced insulin resistance. Here Jia et al.create two tissue-specific Tlr4 knockouts to demonstrate that hepatic Tlr4, but not Tlr4 expressed in myeloid cells, is driving obesity-induced inflammation and insulin resistance.

Melanocortin 4 receptors (MC4Rs) in the CNS regulate metabolism. Here the authors examine extra-hypothalamic MC4Rs in the autonomic nervous system and find that they contribute to energy and glucose homeostasis.

Fibroblast growth factor 21 (FGF21) is a cytokine synthesized and released by the liver, muscle and fat and acts both locally and systemically to regulate whole-body metabolism. David Mangelsdorf and his colleagues now show in two separate studies that FGF21 also acts on the region of the brain that regulates circadian rhythm, the suprachiasmatic nucleus, to further regulate whole-body metabolism as well as reproductive function.

Tan et al. identify a regulatory network between colonic EECs and the gut microbiota that controls l-glutamic acid production, appetite and body weight in mice.

Neurons expressing Agouti-related protein (AgRP) and neuropeptide Y (NPY) in the hypothalamus are involved in regulation of feeding and body weight, but genetic disruption of AgRP and NPY have little effect on energy homeostasis. A new study from Tong et al. shows that the energy homeostasis function is mediated through their GABAergic transmission.

The peptide hormone ghrelin has previously been linked to the regulation of metabolism. This study in mice finds that increasing levels of ghrelin, either through subcutaneous injections or calorie restriction, has an anxiolytic and antidepressive effect. This reveals a previously unknown function for ghrelin.

Excess ketogenesis can lead to ketoacidosis, a serious complication in patients with diabetes. Here the authors report an insulin independent pathway, the hepatic nonparenchymal S100A9-TLR4-mTORC1 axis, that is able to normalize diabetic ketogenesis and pre-clinical data to suggest potential for development of S100A9 based adjunctive therapy to insulin.

PDGFRβ⁺ perivascular mesenchymal cells are shown to regulate chronic adipose-tissue inflammation in obesity through downregulation of ZFP423, a transcriptional corepressor of NF-κB.

The authors report that insulin activates PI3K signaling in SF-1–expressing neurons of the ventromedial hypothalamus to regulate their firing frequency. Mice with insulin receptor deficiency in these neurons show protection from the metabolic effects of exposure to high-fat diet.

Cannabinoid-induced feeding signals are shown to enhance pro-opiomelanocortin (POMC) neuronal activity in mice, causing an enhancement of β-endorphin release, which is crucial in causing this cannabinoid-induced response; these results uncover an overlooked role of hypothalamic POMC neurons in the promotion of feeding by cannabinoids.

Melanocortin 4 receptors (MC4Rs) are critical to the promotion of homeostatic satiety. The authors established paraventricular hypothalamus (PVH) MC4R-expressing neurons as a functional target for orexigenic arcuate nucleus agouti-related peptide–expressing neurons and identify an explicit PVH MC4R-expressing neuron to lateral parabrachial nucleus satiety-promoting circuit, the activation of which encodes positive valence in calorically depleted mice.

The hormone leptin is best known for its influence on body weight. But it also controls bone mass, and recent work in mice is beginning to uncover the neuroendocrine systems involved.

The brain regulates adipose tissue metabolism through sympathetic efferent pathways; in turn, adipose tissues relay energy-status information to the brain. This Review gives an overview of interactions between the brain and adipose tissues, with a particular focus on leptin as a regulator of these communications.

Mice that cannot sense glucose with their pro-opiomelanocortin (POMC neurons) develop glucose intolerance, demonstrating that glucose sensing in neurons plays an important role in responding to a systemic glucose load. It is also shown that in mice with obesity-induced type 2 diabetes, glucose-sensing by POMC neurons is defective.

Is diabetes a disease of the central nervous system? New data point in that direction. Alterations of the levels of long chain fatty acids in the hypothalamus are now shown to influence glucose homeostasis (pages 756–761).

Circuits have been described in the hypothalamus and brainstem involved in regulating feeding and energy balance. In this review, the authors discuss the many peripheral signals that influence these central circuits to affect feeding behavior and energy balance.