Person:

Resch, Jon

Arcuate nucleus (ARC) neurons sense the fed/fasted state and regulate hunger. Agouti-related protein (ARCAgRP) neurons are stimulated by fasting, and once activated, they rapidly (within minutes) drive hunger. Pro-opiomelanocortin (ARCPOMC) neurons are viewed as the counterpoint to ARCAgRP neurons. They are regulated in an opposite fashion and decrease hunger. However, unlike ARCAgRP neurons, ARCPOMC neurons are extremely slow in affecting hunger (many hours). Thus, a temporally analogous, rapid ARC satiety pathway does not exist or is presently unidentified. Here, we show that glutamate-releasing ARC neurons expressing oxytocin receptor, unlike ARCPOMC neurons, rapidly cause satiety when chemo- or optogenetically manipulated. These glutamatergic ARC projections synaptically converge with GABAergic ARCAgRP projections on melanocortin-4 receptor (MC4R)-expressing satiety neurons in the paraventricular hypothalamus (PVHMC4R neurons). Importantly, transmission across the ARCGlutamatergic→PVHMC4R synapse is potentiated by the ARCPOMC neuron-derived MC4R agonist, α-MSH. This excitatory ARC→PVH satiety circuit, and its modulation by α-MSH, provides new insight into regulation of hunger/satiety.

The hypothalamic arcuate-median eminence complex (Arc-ME) controls energy balance, fertility, and growth through molecularly distinct cell types, many of which remain unknown. To catalog cell types in an unbiased way, we profiled gene expression in 20,921 individual cells in and around the adult mouse Arc-ME using Drop-seq. We identify 50 transcriptionally distinct Arc-ME cell populations, including a rare tanycyte population at the Arc-ME diffusion barrier, a novel leptin-sensing neuronal population, multiple AgRP and POMC subtypes, and an orexigenic somatostatin neuronal population. We extended Drop-seq to detect dynamic expression changes across relevant physiological perturbations, revealing cell type-specific responses to energy status, including distinctly responsive subtypes of AgRP and POMC neurons. Finally, integrating our data with human GWAS data implicates two previously unknown neuronal subtypes in the genetic control of obesity. This resource will accelerate biological discovery by providing insights into molecular and cell type diversity from which function can be inferred.

The sympathetic nervous system drives brown and beige adipocyte thermogenesis via release of norepinephrine from local axons. However, the molecular basis underlying the higher levels of sympathetic innervation of thermogenic fat, compared to white fat, has remained elusive. Here we show that thermogenic adipocytes express a previously unknown, mammal-specific endoplasmic reticulum membrane protein, termed Calsyntenin-3β. Genetic loss or gain of Calsyntenin-3β in adipocytes reduces or enhances functional sympathetic innervation in adipose tissue respectively; Calsyntenin-3β ablation predisposes mice to obesity on a high fat diet. Mechanistically, Calsyntenin-3β promotes endoplasmic reticulum localization and secretion from brown adipocytes of S100b, a protein lacking a signal peptide. S100b stimulates neurite outgrowth from sympathetic neurons in vitro. S100b deficiency phenocopies Calsyntenin-3β deficiency, whereas forced expression of S100b in brown adipocytes rescues defective sympathetic innervation caused by Calsyntenin-3β ablation. Taken together, our data elucidate a mammal-specific mechanism of communication between thermogenic adipocytes and sympathetic neurons.