Hydroxycarboxylic acid receptor 2 (HCA2) , formally known as GPR109A, is a metabolite-sensing receptor expressed predominately on adipocytes, immune cells and intestinal epithelial cells. The primary endogenous ligand of HCA2 is β-hydroxybutyrate (βOHB) , which is elevated during periods of nutrient deprivation including fasting. Previous in vitro studies have suggested that βOHB activation of HCA2 on adipocytes inhibits lipolysis and serves as a negative feedback mechanism to prevent excess fat loss during fasting. However, the metabolic implications of this feedback mechanism have not been tested in vivo during a prolonged fast. To address this question, male and female C57BL/6J (WT) and HCA2 knockout (KO) mice were fasted in metabolic cages for 36 hours. No significant differences were observed for genotype or sex in RER, EE, or VO2. Following the fast,KO males exhibited a significant decrease in body weight compared to their WT counterparts. However, body weight was not significantly different between female WT and KO mice after fasting. Gonadal white adipose tissue (gWAT) depot weights were significantly lower in KOmale mice compared to WT male mice, with no significant difference in gWAT weight between female WT and KO mice. Inguinal white adipose tissue (iWAT) depot weights were significantly lower for both sexes in KO mice compared to WT mice. KO males displayed significantly lower levels of circulating NEFAs compared to WT males. However, no differences in NEFAs were observed between female WT and KO mice. No significant differences were shown between groups for glucose, insulin, or βOHB. Therefore, this study demonstrates that mice lacking HCA2 possess a diminished capacity to regulate body and adipose tissue weight during a fast, which is observed to a greater extent in male mice.


K.J.Mccafferty: None. E.Brinker: None. E.Graff: None. T.D.Steury: None. M.W.Greene: None. R.L.Judd: None.

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