Sexually dimorphic role of diet and stress on behavior, energy metabolism, and the ventromedial hypothalamus.

Scientific evidence underscores the influence of biological sex on the interplay between stress and metabolic dysfunctions. However, there is limited understanding of how diet and stress jointly contribute to metabolic dysregulation in both males and females. To address this gap, our study aimed to investigate the combined effects of a high-fat diet (HFD) and repeated footshock stress on fear-related behaviors and metabolic outcomes in male and female mice. Using a robust rodent model that recapitulates key aspects of post-traumatic stress disorder (PTSD), we subjected mice to footshock stressor followed by weekly reminder footshock stressor or no stressor for 14 weeks while on either an HFD or chow diet. Our findings revealed that HFD impaired fear memory extinction in male mice that received initial stressor but not in female mice. Blood glucose levels were influenced by both diet and sex, with HFD-fed female mice displaying elevated levels that returned to baseline in the absence of stress, a pattern not observed in male mice. Male mice on HFD exhibited higher energy expenditure, while HFD-fed female mice showed a decreased respiratory exchange ratio (RER). Sex-specific alterations in pro-inflammatory markers and abundance of hematopoietic stem cells were observed in chronically stressed mice on an HFD in different peripheral tissues, indicating the manifestation of distinct comorbid disorders. Single-nuclei RNA sequencing of the ventromedial hypothalamus from stressed mice on an HFD provided insights into sex-specific glial cell activation and cell-type-specific transcriptomic changes. In conclusion, our study offers a comprehensive understanding of the intricate interactions between stress, diet, sex, and various physiological and behavioral outcomes, shedding light on a potential brain region coordinating these interactions.

Sexually dimorphic role of the locus coeruleus PAC1 receptors in regulating acute stress-associated energy metabolism.

Severe stress leads to alterations in energy metabolism with sexually dimorphic onset or severity. The locus coeruleus (LC) in the brainstem that mediates fight-or-flight-or-freeze response to stress is sexually dimorphic in morphology, plays a key role in interactions between diet and severe stressors, and has neuronal input to the brown adipose tissue (BAT)-a thermogenic organ important for energy balance. Yet, little is known on how LC coordinates stress-related metabolic adaptations. LC expresses receptors for the neuropeptide PACAP (pituitary adenylate cyclase activating peptide) and PACAP signaling through PAC1 (PACAP receptor) are critical regulators of various types of stressors and energy metabolism. We hypothesized that LC-PAC1 axis is a sex-specific central "gatekeeper" of severe acute stress-driven behavior and energy metabolism. Selective ablation of PAC1 receptors from the LC did not alter stress response in mice of either sex, but enhanced food intake in females and was associated with increased energy expenditure and BAT thermogenesis in male mice. These results show a sexually dimorphic role of the LC-PAC1 in regulating acute stress-related energy metabolism. Thus, by disrupting LC-PAC1 signaling, our studies show a unique and previously unexplored role of LC in adaptive energy metabolism in a sex-dependent manner.