Testable hypothesis: Acarbose‑generated propionate activates hepatic mTORC2 via GPR41‑dependent testosterone signaling in male mice

Acarbose extends lifespan in male HET3 mice by ~22% while producing modest benefits in females, a disparity that parallels sex‑specific improvements in glucose tolerance and hepatic mTORC2/Akt/FOXO1a signaling【4】. Although acarbose lowers post‑prandial glucose and raises colonic short‑chain fatty acids (SCFAs) in both sexes【1】【2】, only males show enhanced insulin sensitivity, suggesting that the metabolic arm of longevity is gated by gonadal hormones. We hypothesize that the missing link is a testosterone‑dependent increase in intestinal expression of the SCFA receptor GPR41 (FFAR3), which amplifies propionate‑driven activation of hepatic mTORC2. In this model, acarbose‑induced propionate binds GPR41 on enteroendocrine L‑cells, triggering the release of serotonin and activation of vagal afferents that signal to the nucleus of the solitary tract. The vagal efferent output then increases hepatic insulin signaling via a cholinergic anti‑inflammatory cascade, leading to AKT phosphorylation at Ser473 specifically when androgen receptors are present in hepatocytes. Consequently, mTORC2 signaling rises, FOXO1a is phosphorylated and excluded from the nucleus, and gluconeogenic programs are repressed, yielding the observed male‑specific metabolic improvements. Females lack sufficient androgen‑receptor co‑activation, so despite comparable SCFA elevations, GPR41 signaling fails to potentiate mTORC2, explaining their muted response.

This hypothesis makes three falsifiable predictions: (1) Male mice lacking GPR41 in intestinal epithelium (Villin‑Cre;Gpr41^fl/fl) will lose acarbose‑induced hepatic mTORC2 activation and the associated lifespan extension, while female GPR41 knockouts will show no additional effect beyond baseline; (2) Pharmacologic activation of GPR41 with a selective agonist (e.g., AR420626) will rescue mTORC2 signaling and insulin sensitivity in castrated males treated with acarbose, confirming that receptor activity downstream of SCFA production is sufficient when hormonal context is permissive; (3) Supplementing germ‑free males with propionate alone will not extend lifespan unless testosterone signaling is intact, demonstrating that SCFA production is necessary but not sufficient without hormonal gating. Experiments can be performed using intestinal‑specific Gpr41 floxed mice crossed to Villin‑Cre, gonadectomy regimens, and chronic acarbose feeding, with readouts of hepatic p‑AKT (Ser473), p‑FOXO1a (Thr24/25), glucose tolerance tests, and survival analysis. Additionally, measuring hepatic mTORC2 complex assembly (Rictor immunoprecipitation) and downstream S6K activity will clarify whether the effect is mediated through canonical mTORC2 signaling or parallel AKT activation. If predictions hold, the work would unify the two leading mechanisms of acarbose—glucose blunting and microbiome remodeling—into a single hormone‑gated neuroendocrine axis, clarify the sex dimorphism seen in ITP studies, and suggest that combining acarbose with agents that boost intestinal GPR41 signaling (e.g., prebiotic fibers that increase propionate) could maximize longevity benefits in males while informing sex‑tailored interventions for females.