Beyond appetite regulation: Targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss

New appetite-regulating antiobesity treatments such as semaglutide and agents under investigation such as tirzepatide promise weight loss of 15% or more. Energy expenditure, fat oxidation, and lean mass preservation are essential determinants of weight loss and weight loss maintenance beyond appetite regulation. This review discusses prior failures in clinical development of weight loss drugs targeting energy expenditure and explores novel strategies for targeting energy expenditure: Mitochondrial proton leak, uncoupling, dynamics, and biogenesis: Futile calcium and substrate cycling: Leptin for weight maintenance: Increased sympathetic nervous system activity: Browning of white fat. Relevant targets for preserving lean mass are reviewed: growth hormone, activin type II receptor inhibition, and urocortin 2 and 3. The study endorses moderate modulation of energy expenditure and preservation of lean mass in combination with efficient appetite reduction to obtain a significant, safe, and long-lasting weight loss. Furthermore, the study suggests that the regulatory guidelines should be revisited to focus more on the quality of weight loss and its maintenance rather than the complete weight loss. Commitment to this research focus both from a scientific and a regulatory point of view could signal the beginning of the next era in obesity therapies.