Dataset Information

Alpha2delta-1 in SF1+ Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis.

ABSTRACT: The central mechanisms controlling glucose and lipid homeostasis are inadequately understood. We show that ?2?-1 is an essential regulator of glucose and lipid balance, acting in steroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamus (VMH). These effects are body weight independent and involve regulation of SF1+ neuronal activity and sympathetic output to metabolic tissues. Accordingly, mice with ?2?-1 deletion in SF1 neurons exhibit glucose intolerance, altered lipolysis, and decreased cholesterol content in adipose tissue despite normal energy balance regulation. Profound reductions in the firing rate of SF1 neurons, decreased sympathetic output, and elevated circulating levels of serotonin are associated with these alterations. Normal calcium currents but reduced excitatory postsynaptic currents in mutant SF1 neurons implicate ?2?-1 in the promotion of excitatory synaptogenesis separate from its canonical role as a calcium channel subunit. Collectively, these findings identify an essential mechanism that regulates VMH neuronal activity and glycemic and lipid control and may be a target for tackling metabolic disease.

SUBMITTER: Felsted JA

PROVIDER: S-EPMC5730076 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Publications

Alpha2delta-1 in SF1<sup>+</sup> Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis.

Felsted Jennifer A JA Chien Cheng-Hao CH Wang Dongqing D Panessiti Micaella M Ameroso Dominique D Greenberg Andrew A Feng Guoping G Kong Dong D Rios Maribel M

Cell reports 20171201 10

The central mechanisms controlling glucose and lipid homeostasis are inadequately understood. We show that α2δ-1 is an essential regulator of glucose and lipid balance, acting in steroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamus (VMH). These effects are body weight independent and involve regulation of SF1<sup>+</sup> neuronal activity and sympathetic output to metabolic tissues. Accordingly, mice with α2δ-1 deletion in SF1 neurons exhibit glucose intolerance, altered lipolys ...[more]

PMID: 29212022

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Project description:Objective17β-Estradiol (17βE) regulates glucose homeostasis in part by centrally mediated mechanisms. In female rodents, the influence of the ovarian cycle on hypoglycemia counterregulation and glucose tolerance is unclear. We found previously that in prepubertal females, 17βE modulates glucose sensing in nonadapting glucose-inhibited (GI) and adapting GI (AdGI) neurons within the ventrolateral portion of the ventromedial nucleus (VL-VMN). Nonadapting GI neurons persistently decrease their activity as glucose increases while AdGI neurons transiently respond to a glucose increase. To begin to understand if endogenous fluctuations in estrogen levels across the estrous cycle impact hypothalamic glucose sensing and glucose homeostasis, we assessed whether hypoglycemia counterregulation and glucose tolerance differed across the phases of the estrous cycle. We hypothesized that the response to insulin-induced hypoglycemia (IIH) and/or glucose tolerance would vary throughout the estrous cycle according to changes in 17βE availability. Moreover, that these changes would correlate with estrous-dependent changes in the glucose sensitivity of VL-VMN glucose-sensing neurons (GSNs).MethodsThese hypotheses were tested in female mice by measuring the response to IIH, glucose tolerance and the glucose sensitivity of VL-VMN GSNs during each phase of the estrous cycle. Furthermore, a physiological brain concentration of 17βE seen during proestrus was acutely applied to brain slices isolated on the day of diestrous and the response to low glucose in VL-VMN GSNs was assayed.ResultsThe response to IIH was strongest during diestrous. The response of nonadapting GI and AdGI neurons to a glucose decrease from 2.5 to 0.5mM also peaked during diestrous; an effect which was blunted by the addition of 17βE. In contrast, the glucose sensitivity of the subpopulation of GSNs which are excited by glucose (GE) was not affected by estrous phase or exogenous 17βE application.ConclusionThese data suggest that physiological fluctuations in circulating 17βE levels across the estrous cycle lead to changes in hypothalamic glucose sensing and the response to IIH.

Dataset Information

Alpha2delta-1 in SF1+ Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis.

Publications

Alpha2delta-1 in SF1<sup>+</sup> Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis.

Similar Datasets

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