Obesity by High Fat Diet Decreases the Abundance of MC4R Protein in the Paraventricular Nucleus of the Hypothalamus without Reducing the Number of MC4R Neurons

Abstract

The hypothalamus plays a central role in maintaining normal energy homeostasis. The arcuate nucleus (ARC) of the hypothalamus receives anorexigenic signals from the periphery mediated by increased circulating leptin and insulin, which bind to receptors expressed by proopiomelanocortin (POMC) neurons in the ARC. When activated, POMC neurons projecting to the paraventricular nucleus (PVN) of the hypothalamus release α‐Melanocyte‐stimulating hormone (α‐MSH) at this location. In the PVN, α‐MSH binding to the melanocortin 4 receptor (MC4R) signals to decrease food intake and increase energy expenditure. Exposure to HF diet induces, in male, but not female mice, injury to POMC neurons with neuronal loss and loss of α‐MSH abundance. It remains unclear whether other types of hypothalamic neurons are also being affected by exposure to HF diet. In this respect, we have found that exposure to HF diet induces loss of Single‐Minded Family BHLH Transcription Factor 1 (Sim1) neurons in the PVN of male and female mice. Sim1 neurons in the PVN include the population of MC4R neurons. Here we asked whether in the PVN of mice exposed to HF diet there is a loss of MC4R neurons and/or decreased abundance of MC4R protein. When exposed to HF diet, male and female Sapphire mice expressing GFP under the MC4R have increased body weight as compared to the control mice fed low fat (LF) diet (by 39.03 ± 5.37% and 24.19 ±4.18%, respectively). Both male and female Sapphire mice exposed to HF diet have the same number of MC4R neurons as compare to controls exposed to LF diet. These data indicate that MC4R neurons are resistant to HF diet. To test whether exposure to HF diet reduces the abundance of MC4R protein, we generated knock‐in mice with human influenza hemagglutinin (HA) epitope tag at the C‐terminus of endogenous MC4R (MC4R‐HA mice). As compared to control, male and female MC4R‐HA mice exposed to HF diet had increased body weight (by 53.84 ± 7.00% and 45.57 ± 6.23% respectively), increased caloric intake by (39.28 ± 16% and 37.52 ± 10.85%, respectively) and reduced MC4R protein abundance in the PVN (by 63.27 ± 18.54 % and 67.77 ± 18.00 %). The data indicate that loss of MC4R protein, rather than of MC4R neurons, is a feature of male and female mice exposed to HF diet, thereby suggesting expression of MC4R as a target for anti‐obesity therapy.Support or Funding InformationThis work was supported by National Institutes of Health Grants R01‐DK102206 (to G.B.), by UL1TR000039, and by Intramural Funding Support from the University of Arkansas for Medical Sciences College of Medicine Research Council.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.