Hypothalamic Pomc‐deficiency Impairs the Function of Leptin to Decrease Food Intake and Bodyweight
Authors: Chhabra Kavaljit H , Adams Jessica M , Jones Graham , Rubinstein Marcelo , Low Malcolm J 
Published: November 2023

Proopiomelanocortin (Pomc) in the arcuate nucleus (Arc) of the hypothalamus is necessary for normal energy homeostasis; therefore, its deficiency leads to obesity. We recently reported that ArcPomc‐rescue by genetic intervention prevents obesity in otherwise obesity‐destined ArcPomc‐knockout (KO) mice. However, the efficiency of ArcPomc‐rescue to normalize body weight (BW) was contingent on the magnitude of obesity at the time of genetic intervention. To dissect the molecular mechanism(s) responsible for that observation, we hypothesized that ArcPomc‐rescue mediated reversal of obesity is linked to the function of leptin to reduce BW and food intake (FI). To test our hypothesis, we performed a longitudinal study during which we assessed BW, FI, plasma leptin levels and leptin sensitivity in the same set of ArcPomc‐KO mice when they were obese, weight‐matched to WT mice by calorie restriction, and after ArcPomc rescue. ArcPomc was rescued in the weight‐matched mice by tamoxifen‐inducible Cre recombinase technology. We found that obese KO mice exhibited significantly higher plasma leptin levels (68 ±4.1 vs. 5.6 ±0.4 ng/ml), which were reduced by 78% in the weight‐matched group (14.5 ±1.2 ng/ml) but still remained higher, relative to WT group (P<0.01). Moreover, leptin treatment did not reduce BW relative to saline‐group (Δ BW, 0.52 ±0.06 vs. 0.56 ±0.07 g/24 h when mice were obese; 0.8 ± 0.08 vs 0.6 ±0.07 g/24 h when mice were weight‐matched) and FI (Δ FI, 5.8 ±0.2 vs. 6.1 ±0.1 g/24 h when mice were obese; 6.0 ±0.1 vs. 6.2 ±0.1 g/24 h when mice were weight‐matched) in the KO mice at different stages of the longitudinal study. Remarkably, we found that ArcPomc‐rescue in the weight‐matched KO mice restored normal BW (32.6 ±1.0 g), FI (4.4 ±0.6 g), leptin levels (4.6 ±1.3 ng/ml) and sensitivity [Δ BW, −1.6 ±0.1 (leptin) vs. 0.01 ±0.06 (saline) g/24 h] in the mice that had a history of obesity. In contrast, mice that remained ArcPomc deficient regained massive obesity (BW: 68.4 ±1.5 g, P<0.001) and hyperleptinemia (70.2 ±5.4 ng/ml, P<0.001). To further confirm the association of hypothalamic Pomc with leptin action, we treated weight‐matched ArcPomc KO mice without a history of obesity with leptin. Intraperitoneal and intracerebroventricular leptin administration failed to reduce BW and FI in the KO mice. Interestingly, there was no change in hypothalamic leptin receptor gene expression; however, relative hypothalamic pSTAT3 levels after leptin administration were 20% lower in the KO mice compared to wildtype mice. Altogether, our study suggests that restoration of normal body weight and food intake in ArcPomc KO mice after ArcPomc‐rescue is linked with leptin sensitivity. Moreover, hypothalamic Pomc appears to mediate the function of leptin to control BW and FI. Therefore, stimulating hypothalamic Pomc signaling provides an alternative approach to treat obesity in face of leptin resistance.Support or Funding InformationNIH grants R01 DK066604 (to M.J.L.), R01 DK068400 (to M.J.L. and M.R.). NIH grants P30 DK020572 and P30 DK089503 to University of Michigan Animal Phenotyping and Chemistry Cores supported by the Michigan Diabetes Research Center and the Michigan Nutrition and Obesity Research Center