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PERK in POMC neurons connects celastrol with metabolism
Zhenyan He, … , Ling Hu, Kevin W. Williams
Zhenyan He, … , Ling Hu, Kevin W. Williams
Published September 22, 2021
Citation Information: JCI Insight. 2021;6(18):e145306. https://doi.org/10.1172/jci.insight.145306.
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Research Article Endocrinology Neuroscience

PERK in POMC neurons connects celastrol with metabolism

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Abstract

ER stress and activation of the unfolded protein response in the periphery as well as the central nervous system have been linked to various metabolic abnormalities. Chemically lowering protein kinase R–like ER kinase (PERK) activity within the hypothalamus leads to decreased food intake and body weight. However, the cell populations required in this response remain undefined. In the current study, we investigated the effects of proopiomelanocortin-specific (POMC-specific) PERK deficiency on energy balance and glucose metabolism. Male mice deficient for PERK in POMC neurons exhibited improvements in energy balance on a high-fat diet, showing decreased food intake and body weight, independent of changes in glucose and insulin tolerances. The plant-based inhibitor of PERK, celastrol, increases leptin sensitivity, resulting in decreased food intake and body weight in a murine model of diet-induced obesity (DIO). Our data extend these observations by demonstrating that celastrol-induced improvements in leptin sensitivity and energy balance were attenuated in mice with PERK deficiency in POMC neurons. Altogether, these data suggest that POMC-specific PERK deficiency in male mice confers protection against DIO, possibly providing a new therapeutic target for the treatment of diabetes and metabolic syndrome.

Authors

Zhenyan He, Linh Lieu, Yanbin Dong, Sadia Afrin, Dominic Chau, Anita Kabahizi, Briana Wallace, Jianhong Cao, Eun-Sang Hwang, Ting Yao, Yiru Huang, Jennifer Okolo, Bo Cheng, Yong Gao, Ling Hu, Kevin W. Williams

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Figure 6

Celastrol-induced restoration of leptin sensitivity in POMC neurons from DIO mice requires PERK.

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Celastrol-induced restoration of leptin sensitivity in POMC neurons from...
(A) A leptin-induced (100 nM) depolarization of LepR-expressing POMC neurons from mice fed a chow diet for 8 weeks. (B) Representative leptin-induced (100 nM) depolarization of LepR-expressing POMC neurons from mice fed a HFD for 8 weeks. (C) An example of leptin-induced (100 nM) depolarization of LepR-expressing POMC neurons from mice fed a HFD for 8 weeks and treated with celastrol (i.p., 100 μg/kg, Q.D.) for 2 days. (D) A leptin-induced (100 nM) depolarization of LepR-expressing POMC neurons from mice fed a HFD for 10 months. (E) A leptin-induced (100 nM) depolarization of POMC neurons from POMC-cre:PERKloxp/loxp:tdtomato mice fed a HFD for 10 months. (F) Representative leptin-induced (100 nM) depolarization of POMC neurons from POMC-cre:PERKloxp/loxp:tdtomato mice fed a HFD for 10 months and treated with celastrol (i.p., 100 μg/kg, Q.D.) for 2 days. (G and H) Histograms summarizing the effect of leptin (100 nM) on the membrane potential of POMC neurons from chow-fed and HFD-fed (8 weeks or 10 months) mice, with/without celastrol treatment. (G) The black bar shows the effects of leptin on POMC neurons from mice fed chow for 8 weeks (n = 8). The red bar shows the effects of leptin on POMC neurons from mice fed a HFD for 8 weeks (n = 8). The green bar shows the effects of leptin on POMC neurons from mice fed a HFD for 8 weeks, which were also injected with celastrol (100 μg/kg for 2 days, Q.D., n = 5). (H) The black bar shows the effects of leptin on POMC neurons from mice fed a HFD for 10 months (n = 6). The red bar shows the effects of leptin on POMC neurons from POMC-cre:PERKloxp/loxp:tdtomato mice fed a HFD for 10 months (n = 7). The green bar shows the effects of leptin on POMC neurons from POMC-cre:PERKloxp/loxp:tdtomato mice fed a HFD for 10 months, which also received an injection of celastrol (i.p., 100 μg/kg for 2 days, n = 8). Data are expressed as mean ± SEM. Two-way ANOVA with Tukey’s post hoc analyses, *P < 0.05.

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