Xbp1s in Pomc Neurons Connects ER Stress with Energy Balance and Glucose Homeostasis

Williams, Kevin W.; Liu, Tiemin; Kong, Xingxing; Fukuda, Makoto; Deng, Yingfeng; Berglund, Eric D.; Deng, Zhuo; Gao, Yong; Liu, Tianya; Sohn, Jong Woo; Lin, Jen‐Der; Fujikawa, Teppei; Kohno, Daisuke; Scott, Michael M.; Lee, Syann; Lee, Charlotte E.; Sun, Kai; Chang, Yongsheng; Scherer, Philipp E.; Elmquist, Joel K.

doi:10.1016/j.cmet.2014.06.002

Cited by 223 publications

(247 citation statements)

References 72 publications

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“…As prior work suggests that arcuate neurons mediate the effects of GLP-1 on glucose homeostasis (26), the resistance to the actions of GCG neurons in driving a reduction in glucose production likely occurs in downstream hypothalamic neurons that regulate peripheral hepatic glucose production (52,57). This effect was surprising, however, given data cited earlier that GLP-1R agonism can reverse obesity-driven neuronal insensitivity to hormones such as leptin in arcuate POMC neurons (14,53) to produce a change in food intake.…”

Section: Discussionmentioning

confidence: 99%

“…Of course, it may be that stronger neuronal stimulation of the GCG neurons could produce taste aversion, a hypothesis that should be tested in future work. The potentiation of the anorexic effects of GCG neuronal stimulation in DIO mice when compared with lean animals ( Figure 4D compared with Figure 7A) was surprising, given that ventromedial hypothalamic neurons, which form a principal target of the GCG cells, often become resistant to cues such as leptin and to neuronal stimulation in general that drive a reduction in food intake following HCD feeding (52). However, recent work has shown that peripherally administered liraglutide directly stimulates arcuate pro-opioid melanocortin (POMC) neurons while indirectly inhibiting neuropeptide Y/agouti-related peptide-expressing cells to reduce food intake and body weight in obese mice (14).…”

Section: ]) (B)mentioning

confidence: 96%

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Activation of murine pre-proglucagon–producing neurons reduces food intake and body weight

Gaykema

Newmyer

Ottolini

et al. 2017

Journal of Clinical Investigation

100

156

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Statistics. All data were subjected to statistical analysis in GraphPad Prism 6. When WT and transgene GCG-Gq DREADD mice were compared, 2-tailed unpaired t tests were performed. Time course tests were analyzed with 2-way repeated measures ANOVA with treatment and time points as independent variables. When the same mice received alternating CNO and saline treatments, paired 2-tailed t tests were used to evaluate data for significance. Data from once-performed behavioral tests, such as the open field and elevated plus maze, were analyzed with unpaired 2-tailed t tests. Data are expressed as mean ± SEM. Statistical significance was considered with P < 0.05.Study approval. All animal procedures were approved by the Institutional Animal Care and Use Committee of the University of Virginia and conducted in accordance with its guidelines.

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Section: Discussionmentioning

confidence: 99%

Section: ]) (B)mentioning

confidence: 96%

Activation of murine pre-proglucagon–producing neurons reduces food intake and body weight

Gaykema

Newmyer

Ottolini

et al. 2017

Journal of Clinical Investigation

100

156

View full text Add to dashboard Cite

show abstract

“…Here, by expressing DEPTOR only in POMC neurons, we clearly showed that these cells play a role in modulating brain-liver connection. Interestingly, several groups have reported that POMC neurons are important in the modulation of liver metabolism (2,14,34,38,39). A recent study showed that POMC-specific ablation of p70 S6 kinase 1 (S6K1), a downstream substrate of mTORC1, affects hepatic glucose production and peripheral lipid metabolism without affecting energy balance (35).…”

Section: Discussionmentioning

confidence: 99%

DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance

Caron

Labbé

Mouchiroud

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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-We have recently demonstrated that specific overexpression of DEP-domain containing mTOR-interacting protein (DEPTOR) in the mediobasal hypothalamus (MBH) protects mice against high-fat diet-induced obesity, revealing DEPTOR as a significant contributor to energy balance regulation. On the basis of evidence that DEPTOR is expressed in the proopiomelanocortin (POMC) neurons of the MBH, the present study aimed to investigate whether these neurons mediate the metabolic effects of DEPTOR. Here, we report that specific DEPTOR overexpression in POMC neurons does not recapitulate any of the phenotypes observed when the protein was overexpressed in the MBH. Unlike the previous model, mice overexpressing DEPTOR only in POMC neurons 1) did not show differences in feeding behavior, 2) did not exhibit changes in locomotion activity and oxygen consumption, 3) did not show an improvement in systemic glucose metabolism, and 4) were not resistant to high-fat diet-induced obesity. These results support the idea that other neuronal populations are responsible for these phenotypes. Nonetheless, we observed a mild elevation in fasting blood glucose, insulin resistance, and alterations in liver glucose and lipid homeostasis in mice overexpressing DEP-TOR in POMC neurons. Taken together, these results show that DEPTOR overexpression in POMC neurons does not affect energy balance regulation but could modulate metabolism through a brainliver connection. DEPTOR; mTOR; POMC; energy balance; glucose metabolism THE CONTROL OF FOOD INTAKE and energy expenditure is ensured by neurons of several brain regions, including the mediobasal hypothalamus (MBH), which has emerged as a major center of integration for nutrient and hormonal cues (26,33). MBH hosts several neuronal populations, including the proopiomelanocortin (POMC) and neuropeptide Y (NPY)/agouti-related protein (AgRP)/GABA-producing neurons of the arcuate nucleus, as well as steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamus. Over the years, these neurons were shown to play critical roles in the regulation of systemic metabolic homeostasis (17, 21). Intensive efforts are currently being made to better understand the molecular mechanisms by which MBH neurons control energy balance and systemic metabolism (11, 15).The mechanistic target of rapamycin (mTOR) plays an important role in the hypothalamic regulation of energy balance and glucose homeostasis (3,8,9). mTOR is a serine/threonine kinase that nucleates two protein complexes named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (20). These complexes are part of a well-conserved anabolic pathway that modulates growth and metabolism in response to nutrients and growth factors. They include several proteins, including DEP-domain containing mTOR-interacting protein (DEPTOR), a component of both mTORC1 and mTORC2 (31). Recently, we have characterized the expression of Deptor in the rat and mouse brain and have shown that this gene is highly expressed in several structures involved in energy balance regulation, i...

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“…In rodents, genetic and pharmacological approaches that interfere with such negative regulatory processes promote LEPR-B signaling and thereby resistance to dietinduced obesity [51-53, 64, 79-83]. For example, overexpression of the unfolded protein response transcription factor Xbp1s in POMC neurons decreases PTP1B and SOCS3 expression, improves leptin and insulin sensitivity and liver metabolism and protects against diet-induced obesity [84]. Not surprisingly, deficiencies in neuronal PTP1B and SOCS3…”

Section: Leptin and Insulin Resistancementioning

confidence: 99%

Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling

Zhang

Dodd

Tiganis

2015

Trends in Pharmacological Sciences

153

118

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Xbp1s in Pomc Neurons Connects ER Stress with Energy Balance and Glucose Homeostasis

Cited by 223 publications

References 72 publications

Activation of murine pre-proglucagon–producing neurons reduces food intake and body weight

Activation of murine pre-proglucagon–producing neurons reduces food intake and body weight

DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance

Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling

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