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PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis.

ABSTRACT: Phosphatidyl inositol 3-kinase (PI3K) signaling in the hypothalamus has been implicated in the regulation of energy homeostasis, but the critical brain sites where this intracellular signal integrates various metabolic cues to regulate food intake and energy expenditure are unknown. Here, we show that mice with reduced PI3K activity in the ventromedial hypothalamic nucleus (VMH) are more sensitive to high-fat diet-induced obesity due to reduced energy expenditure. In addition, inhibition of PI3K in the VMH impaired the ability to alter energy expenditure in response to acute high-fat diet feeding and food deprivation. Furthermore, the acute anorexigenic effects induced by exogenous leptin were blunted in the mutant mice. Collectively, our results indicate that PI3K activity in VMH neurons plays a physiologically relevant role in the regulation of energy expenditure.

SUBMITTER: Xu Y

PROVIDER: S-EPMC2919367 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis.

Xu Yong Y Hill Jennifer W JW Fukuda Makoto M Gautron Laurent L Sohn Jong-Woo JW Kim Ki-Woo KW Lee Charlotte E CE Choi Michelle J MJ Lauzon Danielle A DA Dhillon Harveen H Lowell Bradford B BB Zigman Jeffrey M JM Zhao Jean J JJ Elmquist Joel K JK

Cell metabolism 20100701 1

Phosphatidyl inositol 3-kinase (PI3K) signaling in the hypothalamus has been implicated in the regulation of energy homeostasis, but the critical brain sites where this intracellular signal integrates various metabolic cues to regulate food intake and energy expenditure are unknown. Here, we show that mice with reduced PI3K activity in the ventromedial hypothalamic nucleus (VMH) are more sensitive to high-fat diet-induced obesity due to reduced energy expenditure. In addition, inhibition of PI3K ...[more]

PMID: 20620998

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Project description:OBJECTIVE:The cocaine- and amphetamine-regulated transcript (CART) codes for a pivotal neuropeptide important in the control of appetite and energy homeostasis. However, limited understanding exists for the defined effector sites underlying CART function, as discrepant effects of central CART administration have been reported. METHODS:By combining Cart-cre knock-in mice with a Cart adeno-associated viral vector designed using the flip-excision switch (AAV-FLEX) technology, specific reintroduction or overexpression of CART selectively in CART neurons in the arcuate nucleus (Arc) and lateral hypothalamic area (LHA), respectively, was achieved. The effects on energy homeostasis control were investigated. RESULTS:Here we show that CART neuron-specific reintroduction of CART into the Arc and LHA leads to distinct effects on energy homeostasis control. Specifically, CART reintroduction into the Arc of otherwise CART-deficient Cartcre/cre mice markedly decreased fat mass and body weight, whereas CART reintroduction into the LHA caused significant fat mass gain and lean mass loss, but overall unaltered body weight. The reduced adiposity in ArcCART;Cartcre/cre mice was associated with an increase in both energy expenditure and physical activity, along with significantly decreased Npy mRNA levels in the Arc but with no change in food consumption. Distinctively, the elevated fat mass in LHACART;Cartcre/cre mice was accompanied by diminished insulin responsiveness and glucose tolerance, greater spontaneous food intake, and reduced energy expenditure, which is consistent with the observed decrease of brown adipose tissue temperature. This is also in line with significantly reduced tyrosine hydroxylase (Th) and notably increased corticotropin-releasing hormone (Crh) mRNA expressions in the paraventricular nucleus (PVN). CONCLUSIONS:Taken together, these results identify catabolic and anabolic effects of CART in the Arc and LHA, respectively, demonstrating for the first time the distinct and region-specific functions of CART in controlling feeding and energy homeostasis.

Project description:17?-Estradiol (17?E) 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, 17?E 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 17?E availability. Moreover, that these changes would correlate with estrous-dependent changes in the glucose sensitivity of VL-VMN glucose-sensing neurons (GSNs).These 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 17?E 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.The 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 17?E. In contrast, the glucose sensitivity of the subpopulation of GSNs which are excited by glucose (GE) was not affected by estrous phase or exogenous 17?E application.These data suggest that physiological fluctuations in circulating 17?E levels across the estrous cycle lead to changes in hypothalamic glucose sensing and the response to IIH.

Dataset Information

PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis.

Publications

PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis.

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