Origins and Functions of the Ventrolateral VMH: A Complex Neuronal Cluster Orchestrating Sex Differences in Metabolism and Behavior - PubMed (original) (raw)

Review

Origins and Functions of the Ventrolateral VMH: A Complex Neuronal Cluster Orchestrating Sex Differences in Metabolism and Behavior

William C Krause et al. Adv Exp Med Biol. 2017.

Abstract

The neuroendocrine brain or hypothalamus has emerged as one of the most highly sexually dimorphic brain regions in mammals, and specifically in rodents. It is not surprising that hypothalamic nuclei play a pivotal role in controlling sex-dependent physiology. This brain region functions as a chief executive officer or master regulator of homeostatic physiological systems to integrate both external and internal signals. In this review, we describe sex differences in energy homeostasis that arise in one area of the hypothalamus, the ventrolateral subregion of the ventromedial hypothalamus (VMHvl) with a focus on how male and female neurons function in metabolic and behavioral aspects. Because other chapters within this book provide details on signaling pathways in the VMH that contribute to sex differences in metabolism, our discussion will be limited to how the sexually dimorphic VMHvl develops and what key regulators are thought to control the many functional and physiological endpoints attributed to this region. In the last decade, several exciting new studies using state-of-the-art genetic and molecular tools are beginning to provide some understanding as to how specific neurons contribute to the coordinated physiological responses needed by male and females. New technology that combines intersectional spatial and genetic approaches is now allowing further refinement in how we describe, probe, and manipulate critical male and female neurocircuits involved in metabolism.

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Figures

Fig. 1

Fig. 1

Sex-dependent VMH functions are mediated by ERα-expressing VMHvl neurons. Within the hypothalamus, the VMH (red-shaded region) controls multiple aspects of metabolism and behavior. Whereas leptin receptor (LEPR) and insulin receptor (IR) expression overlap with SF-1 and regulate metabolism in both males and females, sex-dependent functions of the VMH are mediated by ERα-expressing VMH neurons (Nissl-stained image adapted from the Allen Brain Atlas)

Fig. 2

Fig. 2

Development of the VMHvl module that modulates energy homeostasis in females. a) ERα immunostaining demonstrates that expression is restricted to the VMHvl in female mice as well as the arcute nucleus (ARC). Fewer VMHERα neurons are born in the _Nkx2-1_Sf1-Cre mutant females (Mutant) compared to _Nkx2-1_fl/fl control females (WT), as described in text. Third ventricle (3V). b) VMHvl neurons do not express SF-1, as illustrated by the lack of GFP-positive neurons using a knock-in reporter (Sf-1)TauGFP. However, Cre-mediated lineage tracing (Z/EG)Sf1:Cre reveals that most VMHvl neurons derive from SF1-expressing precursors. c) Postnatal NKX2-1 expression is largely restricted to ERα-positive and SF-1-negative VMHvl neurons

Fig. 3

Fig. 3

A molecularly distinct subset of VMHERα neurons are necessary and sufficient to drive physical activity in female mice. Chemogenetic activation of VMHvl neurons increases energy expenditure via physical activity in females and requires ERα and TAC1 (left panel). In contrast, reducing the number of VMHERα,TAC1 neurons decreases physical activity and results in female-specific obesity (right panel)

Fig. 4

Fig. 4

Silencing glutamatergic VMH neurons promotes negative energy balance in females. Summary of the relative distribution of VMHVGLUT2 and VMHERα,VGLUT2 neurons and the metabolic consequences resulting from genetic knockout of either ERα or VGLUT2. Opposing metabolic phenotypes observed in mutant female mice following deletion of ERα or VGLUT2 in the VMH suggest that ERα signaling reduces rather than enhances glutamaterigic output from the VMHvl

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