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.
Figures
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
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
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
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
Similar articles
- Selective sexual differentiation of neurone populations may contribute to sex-specific outputs of the ventromedial nucleus of the hypothalamus.
Kammel LG, Correa SM. Kammel LG, et al. J Neuroendocrinol. 2020 Jan;32(1):e12801. doi: 10.1111/jne.12801. Epub 2019 Dec 3. J Neuroendocrinol. 2020. PMID: 31605642 Free PMC article. Review. - Essential and sex-specific effects of mGluR5 in ventromedial hypothalamus regulating estrogen signaling and glucose balance.
Fagan MP, Ameroso D, Meng A, Rock A, Maguire J, Rios M. Fagan MP, et al. Proc Natl Acad Sci U S A. 2020 Aug 11;117(32):19566-19577. doi: 10.1073/pnas.2011228117. Epub 2020 Jul 27. Proc Natl Acad Sci U S A. 2020. PMID: 32719118 Free PMC article. - Androgen receptors are required for full masculinization of the ventromedial hypothalamus (VMH) in rats.
Dugger BN, Morris JA, Jordan CL, Breedlove SM. Dugger BN, et al. Horm Behav. 2007 Feb;51(2):195-201. doi: 10.1016/j.yhbeh.2006.10.001. Epub 2006 Nov 21. Horm Behav. 2007. PMID: 17123532 Free PMC article. - Enhanced male-evoked responses in the ventromedial hypothalamus of sexually receptive female mice.
Nomoto K, Lima SQ. Nomoto K, et al. Curr Biol. 2015 Mar 2;25(5):589-94. doi: 10.1016/j.cub.2014.12.048. Epub 2015 Feb 12. Curr Biol. 2015. PMID: 25683805 - Ventromedial Nucleus of the Hypothalamus Neurons Under the Magnifying Glass.
Khodai T, Luckman SM. Khodai T, et al. Endocrinology. 2021 Oct 1;162(10):bqab141. doi: 10.1210/endocr/bqab141. Endocrinology. 2021. PMID: 34265067 Free PMC article. Review.
Cited by
- Leptin signaling and its central role in energy homeostasis.
Liu Z, Xiao T, Liu H. Liu Z, et al. Front Neurosci. 2023 Oct 31;17:1238528. doi: 10.3389/fnins.2023.1238528. eCollection 2023. Front Neurosci. 2023. PMID: 38027481 Free PMC article. Review. - Sex-specific metabolic adaptations from in utero exposure to particulate matter derived from combustion of petrodiesel and biodiesel fuels.
Jetton TL, Galbraith OT, Peshavaria M, Bonney EA, Holmén BA, Fukagawa NK. Jetton TL, et al. Chemosphere. 2024 Jan;346:140480. doi: 10.1016/j.chemosphere.2023.140480. Epub 2023 Oct 23. Chemosphere. 2024. PMID: 37879369 - Effects of Ventromedial Hypothalamic Nucleus (VMN) Aromatase Gene Knockdown on VMN Glycogen Metabolism and Glucoregulatory Neurotransmission.
Briski KP, Mahmood ASMH, Uddin MM, Ibrahim MMH, Bheemanapally K. Briski KP, et al. Biology (Basel). 2023 Feb 3;12(2):242. doi: 10.3390/biology12020242. Biology (Basel). 2023. PMID: 36829519 Free PMC article. - Hypothalamic neurons that mirror aggression.
Yang T, Bayless DW, Wei Y, Landayan D, Marcelo IM, Wang Y, DeNardo LA, Luo L, Druckmann S, Shah NM. Yang T, et al. Cell. 2023 Mar 16;186(6):1195-1211.e19. doi: 10.1016/j.cell.2023.01.022. Epub 2023 Feb 15. Cell. 2023. PMID: 36796363 Free PMC article. - Sex-dimorphic hindbrain lactate regulation of ventromedial hypothalamic nucleus glucoregulatory neuron 5'-AMP-activated protein kinase activity and transmitter marker protein expression.
Napit PR, Ali MH, Mahmood ASMH, Ibrahim MMH, Briski KP. Napit PR, et al. Neuropeptides. 2023 Jun;99:102324. doi: 10.1016/j.npep.2023.102324. Epub 2023 Feb 2. Neuropeptides. 2023. PMID: 36791640 Free PMC article.
References
- Brailoiu E, Dun SL, Brailoiu GC, Mizou K, Sklar LA, Oprea TI, Prossnitz ER, Dun NJ. Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system. The Journal of Endocrinology. 2007;193:311–321. - PubMed
- Brobeck JR, Wheatland M, Strominger JL. Variations in regulation of energy exchange associated with estrus, diestrus and pseudopregnancy in rats. Endocrinology. 1947;40:65–72. - PubMed
- Brock O, De Mees C, Bakker J. Hypothalamic expression of oestrogen receptor alpha and androgen receptor is sex-, age- and region-dependent in mice. Journal of Neuroendocrinology. 2015;27:264–276. - PubMed
Publication types
MeSH terms
LinkOut - more resources
Full Text Sources
Other Literature Sources