High-Fat Diet Alters Neuronal Activity in Cardiometabolic-Regulatory Brain Regions in a Sex-Specific Manner

Abstract

Obesity is a major public health problem that is associated with dysregulation of central nervous system circuits controlling cardiovascular and metabolic functions. High-fat diet (HFD)-induced obesity in animal models is known to widely influence neuronal function in metabolic-regulatory brain regions; however, the impact of HFD, and its interactions with sex, on neuronal activity in cardiovascular-regulatory brain regions is not fully understood. Thus, the objective of this study was to investigate differences in c-fos expression, a marker of neuronal activity, in key brain regions involved in cardiometabolic regulation in HFD-induced obese mice. We hypothesized that HFD would alter the pattern of neuronal activity in hypothalamic and brainstem regions in a sex-specific manner. To test this, male and female C57Bl/6J mice (n=6/group) were placed on a 60% HFD or matched control diet for 14 weeks. At the end of the diet period, brains were collected to assess for c-fos immunoreactivity in the paraventricular nucleus (PVN) and arcuate nucleus (ARC) of the hypothalamus, as well as in the nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM) of the brainstem. Brain slices were imaged using a Keyence Fluorescent Microscope and c-fos positive cells were counted using QuPath software in a blinded manner. There was a significant effect due to a sex-by-diet interaction in all brain regions, with female mice having a lower number of c-fos positive neurons compared to males overall, and even more so under HFD conditions (PVN: 132±21 male control vs. 183±28 male HFD vs. 136±21 female control vs. 89±10 female HFD, Pdiet=0.916, Psex=0.041, Pint=0.028 two-way ANOVA; ARC: 92±23 male control vs. 108±16 male HFD vs. 90±7 female control vs. 41±6 female HFD, Pdiet=0.272, Psex=0.024, Pint=0.039; NTS: 72±20 male control vs. 114±115 male HFD vs. 68±10 female control vs. 31±6 female HFD, Pdiet=0.885, Psex=0.004, Pint=0.009; RVLM: 59±12 male control vs. 105±11 male HFD vs. 59±12 female control vs. 28±5 female HFD, Pdiet=0.464, Psex=0.002, Pint=0.002). Overall, these data suggest there are sex-specific differences in neuronal activity within key brain regions integral to cardiometabolic control, which may be influenced by HFD in females. Future studies will need to assess the importance of these changes in neural activity to functional outcomes under normal conditions, and in the context of obesity. Funding: NIH R01 HL156986. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.