SUMMARY Activation of Agouti-related peptide (AgRP) neurons potently promotes feeding, and chronically altering their activity also affects peripheral glucose homeostasis. We demonstrate that acute activation of AgRP neurons causes insulin resistance through impairment of insulin-stimulated glucose uptake into brown adipose tissue (BAT). AgRP neuron activation acutely reprograms gene expression in BAT toward a myogenic signature, including increased expression of myostatin. Interference with myostatin activity improves insulin sensitivity that was impaired by AgRP neurons activation. Optogenetic circuitry mapping reveals that feeding and insulin sensitivity are controlled by both distinct and overlapping projections. Stimulation of AgRP → LHA projections impairs insulin sensitivity and promotes feeding while activation of AgRP → anterior bed nucleus of the stria terminalis (aBNST)vl projections, distinct from AgRP → aBNSTdm projections controlling feeding, mediate the effect of AgRP neuron activation on BAT-myostatin expression and insulin sensitivity. Collectively, our results suggest that AgRP neurons in mice induce not only eating, but also insulin resistance by stimulating expression of muscle-related genes in BAT, revealing a mechanism by which these neurons rapidly coordinate hunger states with glucose homeostasis.

Satiety-signaling, pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus play a pivotal role in the regulation of energy homeostasis. Recent studies reported altered mitochondrial dynamics and decreased mitochondria- endoplasmic reticulum contacts in POMC neurons during diet-induced obesity. Since mitochondria play a crucial role in Ca2+ signaling, we investigated whether obesity alters Ca2+ handling of these neurons in mice. In diet-induced obesity, cellular Ca2+ handling properties including mitochondrial Ca2+ uptake capacity are impaired, and an increased resting level of free intracellular Ca2+ is accompanied by a marked decrease in neuronal excitability. Experimentally increasing or decreasing intracellular Ca2+ concentrations reproduced electrophysiological properties observed in diet-induced obesity. Taken together, we provide the first direct evidence for a diet-dependent deterioration of Ca2+ homeostasis in POMC neurons during obesity development resulting in impaired function of these critical energy homeostasis-regulating neurons.DOI: http://dx.doi.org/10.7554/eLife.25641.001

Electronic absorption spectra between 20 000 and 62 000 cm-1 of anthracene-9,10-endoperoxide (APO), its 9,10-dimethyl derivative (DMAPO), and perdeutero-APO isolated in Ar matrices are presented. These spectra are interpreted with the help of semiempirical (INDO/S and CNDO/S) calculations of the electronically excited states. Both experimental and theoretical results lead to an unambiguous assignment of the electronic states of APO and its derivatives. Several higher excited singlet states with significant oscillator strengths have been observed for the first time. The present assignment disagrees with the so far accepted assignment of the electronic states of these APOs, namely, that the first excited singlet state (S1) is located at 23 000 cm-1 and that the photocycloreversion occurs from the higher excited singlet state (S2) at ∼36 000 cm-1. In our new assignment, the first excited singlet state (S1) is located at 36 360 cm-1 and the low-lying triplet states that are predicted by the semiempirical calculations and measured using the heavy atom effect of C2H5I solvent are located at ∼21 000 cm-1. Thus, the present assignment shows that the photocycloreversion of these APOs is not an exception to Kasha's rule. The spectroscopic signature of APO and DMAPO is governed by the exciton-like interactions between the phenyl subunits, which is also reflected in the strikingly similar spectroscopic properties of an isoelectronic molecule of APO, namely, 9,10-dihydro-9,10-ethanoanthracene. Possible reasons for the misinterpretation and/or wrong generalizations carried out in earlier works have been discussed.