Advantage of Semaglutide: Comprehensive Analysis of Metabolic Impact of Semaglutide‐Treated and Pair‐Fed Rats

Semaglutide (SEMA), a GLP-1 receptor agonist, effectively reduces body weight. Yet its mechanisms of action remain incompletely understood. It is unclear whether SEMA promotes weight loss solely through reduced food intake or also through intake-independent mechanisms, and whether these effects differ by sex. To address these questions, we used a pair-feeding design in diet-induced obese rats, comparing SEMA-treated rats with both ad libitum-fed controls and SEMA intake-matched groups over 4-week treatment. Analyses included sex-stratified outcomes, depot-specific brown and white adipose profiling, thermogenesis, locomotor activity, and circulating metabolic hormone measurements. SEMA reduced food intake of both hypercaloric, high-fat/high-sugar diet and chow and produced body weight loss beyond the effects of caloric restriction alone. SEMA also curbed the hunger hormone ghrelin. It reduced visceral adiposity and increased activity, albeit more potently in females compared to males. Across adipose depots SEMA promoted smaller adipocyte size, white adipose tissue browning, and enhanced sympathetic innervation, while these changes were largely absent in pair-fed rats. SEMA rescued caloric restriction-associated hypothermia and small reductions in circulating thyroid hormones; it also potentiated local thyroid input. SEMA induced sex-dependent, depot-specific adipose remodeling and sustained increases in locomotor activity independent of food intake. Our integrative approach provides new insight into SEMA's mechanisms and highlights the importance of evaluating sex as a biological variable in mechanistic studies of obesity therapies. Metabolic benefits of the SEMA treatment far outweighed those offered by comparable caloric restriction, indicating that its mechanism of action involves not only hypophagia but also adipose tissue remodeling and browning.