Tirzepatide reduces body weight by increasing fat utilization via the central nervous system‐adipose tissue axis in male mice

Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, demonstrates promise as a potent medication for obesity. However, the extent to which its weight-reducing effects go beyond suppressing appetite remains unclear. This study aimed to elucidate this by establishing a pair-fed control group, effectively eliminating the influence of reduced caloric intake. Mice fed on a chow diet or a high-fat diet received single or long-term intracerebroventricular (i.c.v.) injections of tirzepatide or vehicle. The vehicle-treated mice were pair-fed to the tirzepatide-treated group to avoid the impact induced by different caloric intakes. Body weight and food intake were monitored daily. Respiratory exchange ratio (RER) was determined in metabolic cages. Fat utilization was calculated based on RER. Parameters of lipid metabolism were evaluated. Mice receiving i.c.v. administration of tirzepatide exhibited significant reductions in body weight and fat content compared with pair-fed controls. These effects were mediated by increased lipolytic capacity in white adipose tissue and enhanced thermogenesis in brown and beige adipose tissues, leading to decreased RER and increased lipid utilization. Mechanistic investigations revealed that these effects were primarily mediated by sympathetic nervous system innervation of adipose tissues. This innervation, in turn, might be associated with the neuronal activity changes in the dorsomedial hypothalamus and the nucleus of the solitary tract within the hindbrain. These findings establish a critical role for tirzepatide in shifting the substrate preference to fat utilization through the central nervous system-adipose tissue axis, promoting weight loss independent of food intake.