AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue

Abstract

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.

Neuronal control of peripheral insulin sensitivity and glucose metabolism

“…By contrast, acute activation of POMC neurons had no effect on glucose metabolism in these studies14, suggesting that acute AgRP neuron activation controls peripheral insulin sensitivity without interfering with the melanocortin pathway. Experiments defining melanocortin-dependent feeding behaviour have shown that the hypophagia from stimulating POMC neurons is prevented in A y mice, in which AgRP constitutively blocks melanocortin signalling.…”

The Dichotomous Effect of Chronic Stress on Obesity

“…Subordinate mice housed at room temperature also show a molecular signature in the BAT characteristic of the myogenic lineage and de-differentiated brown adipocytes [84]. Consistent with a role of AgRP neurons in mediating stress-induced positive energy balance in mice housed at room temperature (see Central mechanisms of stress-induced positive energy balance) , recent data demonstrated that opto- and chemo-genetic activation of ARC-AgRP neurons inhibit sympathetic activity to BAT, increase myogenic markers in the BAT and impair insulin sensitivity [86]. …”

Hunger-Driven Motivational State Competition

“…A complete transcriptional profiling of this subpopulation is currently lacking although it has been shown that LH VGAT neurons are distinct from cells containing the feeding-related neuropeptides melanin-concentrating hormone and orexin (Jennings et al, 2015). Moreover, while several ARC AgRP efferents, which are wired in a one-to-one fashion (Betley et al, 2013), have been assessed for their sufficiency to evoke acute food intake including projections to the bed nucleus of the stia terminalis (BNST), LH, parabrachial nucleus (PBN), amygdala, periaqueductal gray and both the paraventricular thalamus (PVT) and hypothalamus (PVH) (Atasoy et al, 2012; Betley et al, 2013; Padilla et al, 2016; Steculorum et al, 2016), only the LH VGAT →VTA circuit has been analyzed to date and the anatomical architecture including terminal targets and potential collateralization of axons has yet to be described.…”