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Background: TLC-6740, a liver-targeted mitochondrial protonophore, causes dose-dependent weight loss and metabolic benefit in diet-induced obese mice. Here, we evaluated mechanisms of TLC-6740-induced weight loss. Methods: Male C57 BL/6 mice housed at thermoneutrality (28°C) were fed a high-fat diet for 25 wk and dosed with vehicle (Veh) or TLC-6740 (60mg/kg) PO BID for 8 days. Energy expenditure (EE) was measured by indirect calorimetry (Days -1, 1, 6-7) and energy balance was calculated by subtracting EE from energy intake (EI). Results: On Day 1, TLC-6740 increased EE in the dark phase by 18% compared to pre-treatment and by 24% vs Veh (Fig A). EI decreased 26% with TLC-6740 and increased 43% with Veh. Consequently, TLC-6740 induced negative energy balance (Day -1 vs 1: +1.9 vs -1.9 kcal/d) whereas a positive balance was observed with Veh (-0.06 vs +3.4 kcal/d) (Fig B). Respiratory exchange ratio (RER) decreased with TLC-6740, but not Veh, indicating a shift towards increased whole-body lipid utilization (Fig C). Increased EE with TLC-6740 (16% vs Veh) persisted over 6-7 days of dosing leading to 5% weight loss at Day 7. Conclusions: The protonophore TLC-6740 increases EE, inducing negative energy balance and weight loss. These data support evaluation of TLC-6740 for obesity and highlights the complementarity of this mechanism to agents that reduce oral intake (e.g., incretins). Disclosure N. Sroda: Employee; OrsoBio, Inc. A. Vijayakumar: Employee; OrsoBio, Inc. E. Murakami: Employee; OrsoBio, Inc. S. Weng: Employee; OrsoBio, Inc. G.I. Shulman: None. R.P. Myers: Employee; OrsoBio, Inc. M. Subramanian: Board Member; OrsoBio, Inc.
SRODA et al. (Fri,) studied this question.