Molecular Insights Into a Seasonal Switch in Appetite and Body Weight in the 13-Lined Ground Squirrel

Ground squirrels exhibit robust endogenously programmed circannual rhythms of body mass and hibernation. These rhythms are characterized by increased feeding and rapid fattening in the fall when animals become clinically obese prior to the onset of hibernation. Strikingly, before entering hibernation, there is a short ~1-week interval when animals cease feeding (i.e., become hypophagic) and begin to lose body weight, even if food is available. The physiological and neurobiological mechanisms that regulate pre-hibernation fattening and the rapid transition to hypophagia are unclear. We hypothesized that a reduction in energy expenditure facilitates the ability to gain fat in the fall, while a remodeling of hypothalamic neuroendocrine pathways governs the switch to hypophagia prior to entering hibernation. We addressed this by investigating coordinated changes in the physiology of juvenile male and female thirteen-lined ground squirrels (13LGS) during the month preceding hibernation and then measuring changes in peripheral and central gene expression between hyperphagic fattening and hypophagic post-fattening animals. We found that overnight resting metabolic rate and body temperature data decreased across fattening and continued to decline as animals became hypophagic, indicating a reduction in energy expenditure likely facilitates fall-time gains in fat. Gene expression in white adipose tissue and liver confirmed the upregulation of gluconeogenesis and downregulation of adipogenesis in hypophagic post-fattening animals. To determine the mechanisms that allow this rapid fat gain, we peripherally infused the anorectic peptide leptin into fattening animals. Leptin infusions slightly reduced the rate at which body weight was gained in males, with no effect in females, suggesting fattening is facilitated by resistance to peripheral anorectic signals in a sex-dependent manner. Lastly, to assess how neuroendocrine pathways are remodeled that allow a switch to hyperphagia, we microdissected a hypothalamic region involved in controlling energy balance (the arcuate nucleus, median eminence, and third ventricle) and generated bulk RNA-seq data. This data revealed that post-fattening animals downregulated growth factor, retinoic acid, and thyroid hormone transport and signaling processes while upregulating processes related to cell proliferation. These results support a recently proposed hypothesis suggesting a reduction in retinoic acid and thyroid hormone signaling alters cell proliferation processes in the hypothalamus, a mechanism leading to seasonal declines in appetite and body weight. Overall, our study offers insight into the mechanisms that underlie the ability to rapidly gain fat and undergo a programmed reversal from an obese state. Colorado State University Start Up Funding This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.