Selective restoration of neuropeptide leptin signaling in adipose tissue improves vascular function and blood pressure via better glycemic control in male <i>db/db</i> mice only

Objective: While the adipocyte-derived neuropeptide leptin is mainly known for its central control of appetite and energy expenditure, it also acts peripherally to locally control metabolic and cardiovascular organs. However, because of the interconnectedness between metabolic and cardiovascular disorders, whether the cardiovascular effects of leptin are secondary to its metabolic actions or a result of direct signaling in cardiovascular tissues remains unclear. Hypothesis: Based on the protective role of adipocyte leptin signaling for metabolic function, we tested the hypothesis that restoration of adipocyte leptin signaling will improve cardiovascular function in global leptin receptor deficient mice, db/db. Methods: We crossed mice with global transcriptional blockade of leptin receptor ( db loxTB ) with mice expressing Cre recombinase under the control of the adiponectin (APN) promoter to generate a mouse that selectively expresses db in adipocytes ( db /APN + ). Metabolic and cardiovascular functions were concomitantly assessed in male and female db /APN - and db /APN + . Results: We confirmed that male and female db /APN + mice expressed db in visceral (VAT), subcutaneous (SAT), and brown adipose tissue (BAT) and reported that db /APN + females exhibited reduced body weight and SAT, while males db /APN + showed increased BAT weight. However, adipocyte db restoration did not alter total body fat or lean mass in either sex. Increased BAT weight in males db /APN + was associated with enhanced oxygen consumption (VO 2 ) and heat production, measured in Comprehensive Lab Animal Monitoring System (CLAMS), as well as with increased BAT UCP-1 levels. Other markers of adipocyte browning including NFIA, PRDM16, and Elovl3 were also increased in male db /APN + BAT. Interestingly, male db /APN + mice exhibited approximately 5 times higher expression of db in BAT compared to females. However, there was no difference in db expression between males and females in VAT or SAT. Although glucose tolerance test showed trends toward improvement of glucose tolerance in db /APN + in both sexes, HbA1c and insulin sensitivity, as evaluated by insulin tolerance test and plasma insulin levels, were improved in male db /APN + only. This was associated with a significant decrease in the levels of the pro-inflammatory cytokines like TNFα, IFNγ, IL-1β, and IL-17A in male db /APN + mice only. In parallel, adipocyte db restoration improved aortic relaxation to acetylcholine and pulse wave velocity, indicating improved endothelial function and arterial stiffness in males db /APN + . Furthermore, adipocyte db restoration significantly reduced blood pressure in male db /APN + mice only. RT-qPCR analysis of aorta showed decreased expression of inflammation markers, including VCAM1 and TNFα, NOX family members, and of the fibrosis markers collagen 1α1, in male db /APN + mice only. Similarly, db /APN + reduced the expression of inflammation (TNFα and NF-κB) and collagen markers in male mice only, corroborating the improvement in vascular function in male db /APN + . Conclusion: Leptin BAT signaling exerts a significant role in the control of energy expenditure and glycemic control which contributes to the improvement of cardiovascular function via reducing local and systemic inflammation in male mice predominantly. The limited role of BAT leptin in female could be explained by a lower abundance of db. R01HL147639 R01HL155265 R01AR082307 P01HL1605571 R01HL176323 R01HL175471 Uehara Foundation in Japan This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.