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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\u2010independent mechanisms, and whether these effects differ by sex. To address these questions, we used a pair\u2010feeding design in diet\u2010induced obese rats, comparing SEMA\u2010treated rats with both\n                    <jats:italic>ad libitum<\/jats:italic>\n                    \u2010fed controls and SEMA intake\u2010matched groups over 4\u2010week treatment. Analyses included sex\u2010stratified outcomes, depot\u2010specific brown and white adipose profiling, thermogenesis, locomotor activity, and circulating metabolic hormone measurements. SEMA reduced food intake of both hypercaloric, high\u2010fat\/high\u2010sugar 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\u2010fed rats. SEMA rescued caloric restriction\u2010associated hypothermia and small reductions in circulating thyroid hormones; it also potentiated local thyroid input. SEMA induced sex\u2010dependent, depot\u2010specific 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.\n                  <\/jats:p>","DOI":"10.1002\/cph4.70083","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T14:14:17Z","timestamp":1765980857000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Advantage of Semaglutide: Comprehensive Analysis of Metabolic Impact of Semaglutide\u2010Treated and Pair\u2010Fed Rats"],"prefix":"10.1002","volume":"15","author":[{"given":"Suyeun","family":"Byun","sequence":"first","affiliation":[{"name":"Department of Nutritional Sciences Pennsylvania State University  State College Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan 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