Collective and Individual Functions of Leptin Receptor Modulated Neurons Controlling Metabolism and Ingestion

Wall, Esther van de; Leshan, Rebecca L.; Xu, Allison; Balthasar, Nina; Coppari, Roberto; Liu, Shun Mei; Jo, Young Hwan; MacKenzie, Robert G.; Allison, David B.; Dun, Nae J.; Elmquist, Joel K.; Lowell, Bradford B.; Barsh, Gregory S.; Luca, Carl de; Myers, Martin G.; Schwartz, Gary J.; Chua, Streamson C.

doi:10.1210/en.2007-1132

Cited by 296 publications

(279 citation statements)

References 37 publications

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“…We have previously shown that SOCS3 expression is Cre-dependent, and its expression is upregulated approximately twofold in Cre-expressing cells upon recombination (6). The Tg.Agrp-Cre mice have been used and validated in a number of independent studies (7,(25)(26)(27)(28)(29)(30)(31). The resultant mutant mice, termed AgRP-SOCS3-OE, were born in Mendelian ratio with no detectable gross abnormalities.…”

Section: Expression Of Socs3 In Agrp Neurons Is Dynamically Modulated Inmentioning

confidence: 99%

Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

Olofsson

Unger

Cheung

et al. 2013

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

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123

111

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Chronic consumption of a fat-rich diet leads to attenuation of leptin signaling in hypothalamic neurons, a hallmark feature of cellular leptin resistance. To date, little is known about the temporal and spatial dysregulation of neuronal function under conditions of nutrient excess. We show that agouti-related protein (AgRP)-expressing neurons precede proopiomelanocortin neurons in developing diet-induced cellular leptin resistance. High-fat diet-induced up-regulation of suppressor of cytokine signaling-3 (SOCS3) occurs in AgRP neurons before proopiomelanocortin and other hypothalamic neurons. SOCS3 expression in AgRP neurons increases after 2 d of high-fat feeding, but reduces after switching to a low-fat diet for 1 d. Consistently, transgenic overexpression of SOCS3 in AgRP neurons produces metabolic phenotypes resembling those observed after short-term high-fat feeding. We further show that AgRP neurons are the predominant cell type situated outside the blood-brain barrier in the mediobasal hypothalamus. AgRP neurons are more responsive to low levels of circulating leptin, but they are also more prone to development of leptin resistance in response to a small increase in blood leptin concentrations. Collectively, these results suggest that AgRP neurons are able to sense slight changes in plasma metabolic signals, allowing them to serve as first-line responders to fluctuation of energy intake. Furthermore, modulation of SOCS3 expression in AgRP neurons may play a dynamic and physiological role in metabolic fine tuning in response to short-term changes of nutritional status.M ost common forms of obesity, including diet-induced obesity, are associated with hyperleptinemia and impairment of leptin signaling in hypothalamic neurons, the hallmark feature of cellular leptin resistance. Suppressor of cytokine signaling-3 (SOCS3), a direct transcriptional product of STAT3, is up-regulated in the hypothalamus of diet-induced obese animals (1, 2). Mice with heterozygous mutation of the Socs3 gene, neuronal, or proopiomelanocortin (POMC)-specific deletion of the Socs3 gene are hypersensitive to leptin and resistant to diet-induced obesity (3-5). Conversely, up-regulation of SOCS3 in POMC neurons of chow-fed mice leads to increased body adiposity (6). In addition, wide-spread up-regulation of SOCS3 has been shown to be associated with neuronal inflammation in diet-induced obese animals (7). Thus SOCS3, which is up-regulated in chronic obesity, is commonly thought to play a pathophysiological role in obesity-associated leptin resistance.Multiple neuronal subtypes in several regions of the hypothalamus, including the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and lateral hypothalamic area, have been implicated in the regulation of energy balance and leptin action (8,9). A number of hypothalamic neurons and extrahypothalamic neurons express functional leptin receptor (10, 11). Among these neurons, POMC and agouti-related protein (AgRP) neurons are two key arcuate neuronal subtypes. POMC and AgRP neu...

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Section: Expression Of Socs3 In Agrp Neurons Is Dynamically Modulated Inmentioning

confidence: 99%

Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

Olofsson

Unger

Cheung

et al. 2013

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

Self Cite

123

111

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“…Instead, we speculate that excess delivery of lipoproteins secondary to enhanced accumulation of plasma lipoproteins might contribute to hepatic triglyceride accumulation in LEPR-defi cient mice. Another possibility is that these mice have reduced oxidation of triglycerides due to decreased leptin signaling ( 45 ).…”

Section: Leptin Receptor Defi Ciency Affects Plasma and Tissue Lipid mentioning

confidence: 99%

“…First db/db mice have reduced lipoprotein lipase activity ( 52 ), thereby reducing lipoprotein catabolism, while promoting hyperlipidemia. Second, total lipid oxidation is reduced in db/db mice and other cell-specifi c LEPR defi ciencies, causing an accumulation of fat ( 45 ). Overall decreases in lipid utilization would promote lipid accumulations in serum and tissue.…”

Section: Leptin Receptor Defi Ciency Affects Plasma and Tissue Lipid mentioning

confidence: 99%

An intrinsic gut leptin-melanocortin pathway modulates intestinal microsomal triglyceride transfer protein and lipid absorption

Iqbal

Chang

et al. 2010

Journal of Lipid Research

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Supplementary key words MTP • apoB • fat absorption • leptin receptor • POMC • AGRPDietary fat is a major source of energy. Biosynthesis of apolipoprotein B (apoB)-containing lipoproteins in the gut is required for the absorption of fat into the body. Biosynthesis of apoB-containing lipoproteins is critically dependent on the activity of microsomal triglyceride transfer protein (MTP) that mainly resides in the lumen of the endoplasmic reticulum. MTP physically binds to apoB and transfers lipids from membranes/lipid droplets to nascent apoB. These activities are believed to play critical roles in the lipidation of nascent apoB and in the formation of primordial lipoprotein particles ( 1 ). ApoB and MTP are also expressed in the liver to mobilize hepatic triacylglycerol by synthesizing very low density lipoproteins ( 2-4 ). Regulation of MTP expression at transcriptional and posttranscriptional levels is a major determinant of hepatic and intestinal fat mobilization ( 5 ), and recent evidence indicates that MTP expression is differentially regulated in the liver and intestine ( 6 ). For example, hepatic, but not intestinal, MTP is increased by peroxisome proliferator-activated receptor ␣ (PPAR ␣ ) agonists ( 7 ). In the intestine, but not in the liver, inositol-requiring enzyme 1 ␤ (IRE1 ␤ ) has been suggested to posttranscriptionally degrade MTP mRNA ( 6 ). Specifi c intestinal inhibition of MTP is considered a viable therapeutic approach to lower plasma

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“…Deletion of leptin receptors on AgRP neurons increases body weight and adiposity [276]. When leptin receptors were deleted from both POMC and AgRP neurons, the mice became more obese, leading the authors to conclude that POMC and AgRP neurons work synergistically in response to leptin [276]. Insulin also acts on AgRP neurons in the arcuate nucleus [141,189].…”

Section: Agrp/npy Neuronsmentioning

confidence: 99%

Neuroendocrine control of satiation

Asarian¹,

Bächler

2014

Hormone Molecular Biology and Clinical Investigation

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Abstract:Eating is a simple behavior with complex functions. The unconscious neuroendocrine process that stops eating and brings a meal to its end is called satiation. Energy homeostasis is mediated accomplished through the control of meal size via satiation. It involves neural integrations of phasic negative-feedback signals related to ingested food and tonic signals, such as those related to adipose tissue mass. Energy homeostasis is accomplished through adjustments in meal size brought about by changes in these satiation signals. The best understood meal-derived satiation signals arise from gastrointestinal nutrient sensing. Gastrointestinal hormones secreted during the meal, including cholecystokinin, glucagon-like peptide 1, and PYY, mediate most of these. Other physiological signals arise from activation of metabolic-sensing neurons, mainly in the hypothalamus and caudal brainstem. We review both classes of satiation signal and their integration in the brain, including their processing by melanocortin, neuropeptide Y/agouti-related peptide, serotonin, noradrenaline, and oxytocin neurons. Our review is not comprehensive; rather, we discuss only what we consider the best-understood mechanisms of satiation, with a special focus on normally operating physiological mechanisms.

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Collective and Individual Functions of Leptin Receptor Modulated Neurons Controlling Metabolism and Ingestion

Cited by 296 publications

References 37 publications

Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

An intrinsic gut leptin-melanocortin pathway modulates intestinal microsomal triglyceride transfer protein and lipid absorption

Neuroendocrine control of satiation

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