Appropriate Inhibition of Orexigenic Hypothalamic Arcuate Nucleus Neurons Independently of Leptin Receptor/STAT3 Signaling

Münzberg, Heike; Jobst, Erin E; Bates, Sarah H.; Jones, Justin C.; Villanueva, Eneida C.; Leshan, Rebecca L.; Bjornholm, Maria; Elmquist, Joel K.; Sleeman, Mark W.; Cowley, Michael A.; Myers, Martin G.

doi:10.1523/jneurosci.3168-06.2007

Cited by 74 publications

(73 citation statements)

References 45 publications

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“…Leptin (100 nM) increased the firing rate in 12 of 13 POMC neurons (artificial cerebrospinal fluid [ACSF], 1.2 ± 0.1 Hz; leptin, 3.4 ± 0.4 Hz; n = 12, P = 0.00003; Figure 1A). Similar to previous reports, the leptin-induced increase in firing rate was reversible within approximately 15 minutes (12,13,31,32). The selective PI3K antagonist wortmannin (100 nM) was used to delineate a PI3K contribution to the leptin-induced excitation of POMC neurons.…”

Section: Pi3k Blockade Inhibits Leptin-induced Activation Of Pomc Neusupporting

confidence: 57%

Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice

Hill¹,

Williams²,

Ye³

et al. 2008

J. Clin. Invest.

301

320

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Normal food intake and body weight homeostasis require the direct action of leptin on hypothalamic proopiomelanocortin (POMC) neurons. It has been proposed that leptin action requires PI3K activity. We therefore assessed the contribution of PI3K signaling to leptin's effects on POMC neurons and organismal energy balance. Leptin caused a rapid depolarization of POMC neurons and an increase in action potential frequency in patch-clamp recordings of hypothalamic slices. Pharmacologic inhibition of PI3K prevented this depolarization and increased POMC firing rate, indicating a PI3K-dependent mechanism of leptin action. Mice with genetically disrupted PI3K signaling in POMC cells failed to undergo POMC depolarization or increased firing frequency in response to leptin. Insulin's ability to hyperpolarize POMC neurons was also abolished in these mice. Moreover, targeted disruption of PI3K blunted the suppression of feeding elicited by central leptin administration. Despite these differences, mice with impaired PI3K signaling in POMC neurons exhibited normal long-term body weight regulation. Collectively, these results suggest that PI3K signaling in POMC neurons is essential for leptin-induced activation and insulin-induced inhibition of POMC cells and for the acute suppression of food intake elicited by leptin, but is not a major contributor to the regulation of long-term organismal energy homeostasis.

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Section: Pi3k Blockade Inhibits Leptin-induced Activation Of Pomc Neusupporting

confidence: 57%

Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice

Hill¹,

Williams²,

Ye³

et al. 2008

J. Clin. Invest.

301

320

View full text Add to dashboard Cite

show abstract

“…Serum leptin levels in normal subjects are of 11.5 (6.35 -20) ng/mL and in obese adults, 22 (13.5 -44) ng/mL, i.e., the serum leptin levels are significantly increased in obeses [83]. At the level in the arcuate nucleus of the hypothalamus revascularized by the omentum [5,19,84], leptin exerts an inhibitory action on the leptin receptor in the neuropeptide Y (NPY) and Agouti-relat-…”

Section: Leptinmentioning

confidence: 99%

Therapeutic Methods Against Insulin Resistance

Rafael¹

2016

J Endocrinol Metab

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Clinical, neurosurgical and autopsy findings show that type 2 diabetes mellitus is caused by progressive ischemia in the anterior hypothalamus and endocrine pancreas due to atherosclerosis, and associated with insulin resistance. The hypothalamic ischemia provokes neuroendocrinological disorders through descending projections, and the pancreatic ischemia causes an inappropriate insulin secretion. Both ischemic structures can be improved by means of omental implantation (omental transplantation or transposition) or with anti-inflammatory drugs. Likewise, experimental and clinical observations suggest that insulin resistance is caused by inflammatory action of tumor necrosis factor alpha and resistin in the insulin receptor. Because, in contrast to this, high-dose aspirin or resveratrol can reduce hyperglycemia to normal or near normal in diabetic patients. That is, both drugs are almost specific for the treatment of insulin resistance. Finally, the use of clonazepam at night can have a beneficial effect on glucose homeostasis, because it can reduce the effects of stressful stimuli and normalize the sleep disorders or loss.

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“…The indirect nature of AgRP/NPY regulation via ER␣ prompted us to investigate whether estrogen would suppress AgRP/NPY function by inhibiting their neuronal activities. It is known that AgRP/NPY neurons are activated upon fasting, which is associated with dramatic induction of c-Fos expression in these neurons (25). By using Tg.NPY-hrGFP mice, we found that c-Fos expression was barely detectable in AgRP/NPY neurons in fed females (Fig.…”

Section: E2 Inhibits Fasting-induced C-fos Activation In Agrp/npy-neumentioning

confidence: 99%

Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake

Olofsson

Pierce²,

Xu³

2009

Proc. Natl. Acad. Sci. U.S.A.

151

123

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In female mammals including rodents and humans, feeding decreases during the periovulatory period of the ovarian cycle, which coincides with a surge in circulating estrogen levels. Ovariectomy increases food intake, which can be normalized by estrogen treatment at a dose and frequency mimicking those during the estrous cycle. Furthermore, administration of estrogen to rodents potently inhibits food intake. Despite these well-known effects of estrogen, neuronal subtypes that mediate estrogen's anorexigenic effects have not been identified. In this study, we show that changes in hypothalamic expression of agouti-related protein (Agrp) and neuropeptide Y (Npy) coincide with the cyclic changes in feeding across the estrous cycle. These cyclic changes in feeding are abolished in mice with degenerated AgRP neurons even though these mice cycle normally. Central administration of 17␤-estradiol (E2) decreases food intake in controls but not in mice lacking the AgRP neurons. Furthermore, E2 treatment suppresses fastinginduced c-Fos activation in AgRP and NPY neurons and blunts the refeeding response. Surprisingly, although estrogen receptor alpha (ER␣) is the key mediator of estrogen's anorexigenic effects, we find that expression of ER␣ is completely excluded from AgRP and NPY neurons in the mouse hypothalamus, suggesting that estrogen may regulate these neurons indirectly via presynaptic neurons that express ER␣. This study indicates that neurons coexpressing AgRP and NPY are functionally required for the cyclic changes in feeding across estrous cycle and that AgRP and NPY neurons are essential mediators of estrogen's anorexigenic function.estrogen ͉ feeding P roper regulation of energy homeostasis and reproduction is fundamental for fitness and survival. Reproduction is an energy intensive process, and precise interaction of regulators for energy balance and reproduction allows coordinated regulation of these two processes. Leptin, a hormone secreted from adipose tissue, plays a critical role in both energy balance and reproduction. Leptin is produced proportional to body fat mass and it conveys the abundance of the body's energy stores to the brain, where it acts to regulate feeding and energy expenditure (1). A decline in leptin level signals a state of negative energy balance, which triggers robust counterregulatory mechanisms to increase feeding. One consequence of negative energy balance is induction of hypogonadonism and inhibition of reproductive function (2). Consistent with this notion, leptin deficiency results in profound hyperphagia and infertility in rodents and humans (1,(3)(4)(5).Estrogen, a hormone essential for sexual reproduction, plays a role in feeding and energy balance regulation. Serum levels of estrogen decline during negative energy balance (6) and estrogen deficiency or loss of function of estrogen receptor (ER) results in increased feeding and adiposity in rodents and humans (7-10). Feeding and body weight increase in ovariectomized females and estrogen replacement reverses such effects (11,1...

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Appropriate Inhibition of Orexigenic Hypothalamic Arcuate Nucleus Neurons Independently of Leptin Receptor/STAT3 Signaling

Cited by 74 publications

References 45 publications

Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice

Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice

Therapeutic Methods Against Insulin Resistance

Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake

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