Multiple hypothalamic circuits sense and regulate glucose levels

Abstract

The hypothalamus monitors body energy status in part through specialized glucose sensing neurons that comprise both glucose-excited and glucose-inhibited cells. Here we discuss recent work on the elucidation of neurochemical identities and physiological significance of these hypothalamic cells, including caveats resulting from the currently imprecise functional and molecular definitions of glucose sensing and differences in glucose-sensing responses obtained with different experimental techniques. We discuss the recently observed adaptive glucose-sensing responses of orexin/hypocretin-containing neurons, which allow these cells to sense changes in glucose levels rather than its absolute concentration, as well as the glucose-sensing abilities of melanin-concentrating hormone, neuropeptide Y, and proopiomelanocortin-containing neurons and the recent data on the role of ventromedial hypothalamic steroidogenic factor-1 (SF-1)/glutamate-containing cells in glucose homeostasis. We propose a model where orexin/hypocretin and SF-1/glutamate neurons cooperate in stimulating the sympathetic outflow to the liver and pancreas to increase blood glucose, which in turn provides negative feedback inhibition to these cells. Orexin/hypocretin neurons also stimulate feeding and reward seeking and are activated by hunger and stress, thereby providing a potential link between glucose sensing and goal-oriented behavior. The cell-type-specific neuromodulatory actions of glucose in several neurochemically distinct hypothalamic circuits are thus likely to be involved in coordinating higher brain function and behavior with autonomic adjustments in blood glucose levels.

Fig. 1.

Adaptive glucose-sensing in orexin/hypocretin neurons. A: identification of an orexin/hypocretin neuron in a mouse brain slice by postrecording immunocytochemistry (left, orexin cell labelled with Neurobiotin is arrowed; right, the same arrowed cell is labelled with an orexin-A antibody). Scale bar = 50 μm; both images are shown at the same magnification. B: a mouse orexin/hypocretin cell is transiently inhibited by glucose but then adapts its membrane potential back to baseline despite the continuing presence of elevated glucose. C: this adaptation allows an orexin/hypocretin cell to respond to a second change in glucose levels. (Composited from Figs. 1, 4, and 5 of Ref. with permission from Proc Natl Acad Sci USA).

Fig. 2.

Hypothetical model integrating the physiological roles of glucose-inhibited lateral hypothalamus (LH) and ventromedial hypothalamus (VMH) neurons (see text for details). Arrows indicate stimulation (or increased levels), t-bars show inhibition. VTA, ventral tegmental area; LC, locus coeruleus; TMN, hypothalamic tuberomammillary nucleus; CRF, corticotropin-releasing factor; SF-1 steroidogenic factor-1.