Proopiomelanocortin Processing in the Hypothalamus Is Directly Regulated by Saturated Fat: Implications for the Development of Obesity.
In outbred mice, susceptibility or resistance to diet-induced obesity is associated with rapid changes in hypothalamic proopiomelanocortin (POMC) levels. Here, we evaluated 3 hypotheses that potentially explain the development of the different obesity phenotypes in outbred Swiss mice. First, rapid and differential changes in the gut microbiota in obesity-prone (OP) and obesity-resistant (OR) mice fed on a high-fat diet (HFD) might cause differential efficiencies in fatty acid harvesting leading to changes in systemic fatty acid concentrations that in turn affect POMC expression and processing. Second, independently of the gut microbiota, OP mice might have increased blood fatty acid levels after the introduction of a HFD, which could affect POMC expression and processing. Third, fatty acids might act directly in the hypothalamus to differentially regulate POMC expression and/or processing in OP and OR mice. We evaluated OP and OR male Swiss mice using 16S rRNA sequencing for the determination of gut microbiota; gas chromatography for blood lipid determination; and immunoblot and real-time polymerase chain reaction for protein and transcript determination and indirect calorimetry. Some experiments were performed with human pluripotent stem cells differentiated into hypothalamic neurons. We did not find evidence supporting the first 2 hypotheses. However, we found that in OP but not in OR mice, palmitate induces a rapid increase in hypothalamic POMC, which is followed by increased expression of proprotein convertase subtilisin/kexin type 1 PC1/3. Lentiviral inhibition of hypothalamic PC1/3 increased caloric intake and body mass in both OP and OR mice. In human stem cell-derived hypothalamic cells, we found that palmitate potently suppressed the production of POMC-derived peptides. Palmitate directly regulates PC1/3 in OP mice and likely has a functional impact on POMC processing.
['Razolli|Daniela S|DS|', 'de Araújo|Thiago M|TM|', 'Sant Apos Ana|Marcella R|MR|', 'Kirwan|Peter|P|', 'Cintra|Dennys E|DE|', 'Merkle|Florian T|FT|', 'Velloso|Licio A|LA|']
D000818:Animals D059305:Diet, High-Fat D004195:Disease Models, Animal D000069196:Gastrointestinal Microbiome D006801:Humans D007031:Hypothalamus D007249:Inflammation D019787:Linoleic Acid D008297:Male D051379:Mice D009474:Neurons D009765:Obesity D010168:Palmitates D039904:Pluripotent Stem Cells D011333:Pro-Opiomelanocortin D012336:RNA, Ribosomal, 16S
Fatty acid Stem cell Hormone Neurotransmitter