β-Guanidinopropionic Acid (β-GPA) is a creatine analog shown to decrease cellular ATP. Consumption of a diet containing β-GPA induces weight loss, torpor, and a drop in plasma leptin in laboratory mice despite increasing food consumption. We hypothesized that β-GPA-induced weight loss—and the concomitant drop in plasma leptin—promote torpor induction. To test this hypothesis, ob/ob mice (leptin-deficient) and controls (ob/+) were implanted with core body temperature (Tb) telemeters and placed into one of three groups for 16 days: normal chow, chow containing 1% β-GPA ad libitum, and caloric restriction to match body weight loss. In the first 24 hours of β-GPA feeding, ob/ob mice ate a comparable amount of food to ob/ob mice on chow (10.4 ± 0.6 g and 10.1 ± 0.6 g, respectively), whereas calorically restricted mice consumed only 2 g. Over the same 24 hour period, ob/ob mice in both experimental groups entered torpor (β-GPA minimum Tb of 30.3 ± 1.4°C; caloric restriction 28.7 ± 1.5°C) with minimal weight loss (0.7 ± 0.2 g; 0.3 ± 0.6 g respectively), whereas fully fed ob/ob mice did not go into torpor (minimum Tb of 33.4 ± 0.6°C). Control mice on β-GPA did not exhibit any torpor bouts until day 5 (minimum Tb of 29.4 ± 1.0°C), at which point weight loss was 13% of the starting weight. Throughout the 16-day experiment, there was sustained body weight loss in the ob/ob mice on β-GPA and caloric restriction (9.9 ± 1.6 g, p0.05 v β-GPA). The mice on β-GPA consumed more calories (353 ± 29 kcal) than the caloric restriction cohort (112 kcal). Together, these results in ob/ob mice indicate that β-GPA’s induction of weight loss and torpor are leptin-independent. The observed delay in torpor induction in β-GPA-fed control mice (with endogenous leptin) supports the hypothesis that weight loss, and not acute β-GPA effects, promotes torpor induction. In fact, these findings suggest a weight loss threshold required to induce torpor in mice with intact leptin signaling. Future work will determine whether the accelerated weight loss associated with β-GPA treatment is healthy or unhealthy and how the metabolic effects of β-GPA influence torpor incidence and quality. This study was internally funded by Williams College. Data are shown as mean ± standard error. This abstract was presented at the American Physiology Summit 2026 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.
Sheppard et al. (Fri,) studied this question.