Regulation of food intake, insulin sensitivity and sympathetic nerve traffic by hypothalamic steroidogenic factor 1 neurons

Abstract

The ventromedial nucleus of the hypothalamus (VMH) was the first site to be recognized as a key player in body weight regulation. The VMH has also been implicated in brown adipose tissue (BAT) thermoregulation, sympathetic nerve activity and glucose homeostasis. Within the VMH, neurons expressing steroidogenic factor 1 (SF1) which are equipped with receptors that binds various hormonal signals have emerged as key mediators of metabolic control. In this study, we assessed how Designer Receptors Exclusively Activated by Designer Drugs (DREADD)‐mediated activation of SF1 neurons affect food intake, glucose homeostasis, insulin sensitivity and sympathetic nerve activity. Injection of an adeno‐associated virus expressing a Cre‐dependent mCherry tagged‐hM3Dq (AAV‐hM3Dq) into the VMH of SF1Cre+ mice led to VMH‐restricted expression of mCherry validating our strategy. In SFCre+ male mice, DREADD‐mediated activation of SF1 neurons caused a dramatic feeding stimulatory response within 4h of CNO injection (0.75±0.16g relative to 0.13±0.07g in control SF1Cre− mice, P<0.05). Interestingly, in male mice SF1 neuron‐specific activation induces BAT sympathetic nerve activation without affecting renal sympathetic tone. In female mice, food intake and BAT sympathetic traffic were not altered after activation of SF1 neurons. On the other hand, insulin sensitivity was significantly attenuated only in females following SF1 neuron activation (100.20±13.07mmol/L vs 25.25±12.15mmol/L in control at 2h, P<0.05). Glucose homeostasis was not affected upon SF1 neuron activation in both male and female mice. These results show that VMH SF1 neurons regulate food intake, sympathetic tone and insulin sensitivity in a sex‐specific manner. Our findings also provide new insight into a previously unappreciated role of VMH SF1 neuron in the differential control of regional sympathetic nerve traffic.