(P31-076-23) Thermoregulation of Glycolytic Beige Adipose Tissue in Diet-induced Obese Male UCP1 Deficient Mice

Objectives: Limited amounts of brown adipose tissue and large amounts of inflamed white adipose tissue (WAT) have been implicated in the pathogenesis of human obesity. Thus, research efforts have focused on inducing a thermogenic beige fat within WAT to reduce obesity and associated diseases. Although uncoupling protein 1 (UCP1) is a master thermogenic regulator, it has been proposed that a non-canonical glycolytic (g) beige fat from Myod-expressing progenitors with enhanced glucose metabolism, can be activated independently of UCP1. We recently reported that UCP1 knockout (KO) male mice develop beige fat in subcutaneous WAT (SAT) at ambient temperature, but not at thermoneutrality. Therefore, our objective is to investigate whether cold stress induces g-beige fat in absence of UCP1. Accordingly, we hypothesized that ambient temperature promotes g-beige adipocytes biogenesis in SAT of UCP1 KO male mice via myogenic mechanisms.

Methods: Male UCP1 KO and wild type (WT) B6 littermates were housed at ambient or thermoneutral temperatures and fed a 45% high-fat diet for 14 weeks. Body weight and composition were measured. At termination, SAT was collected for RNA sequencing (RNA-seq), followed by pathway analyses and validation of genes using real-time PCR. Data were analyzed by two-way ANOVA using GraphPad Prism.

Results: UCP1 KO mice were resistant to diet-induced obesity at ambient temperature. Moreover, RNA-seq in SAT revealed many genes involved in thermogenesis, glycolysis, and myogenesis which were enriched in UCP1 KO mice, compared to WT, housed at ambient temperature, indicating the presence of g-beige fat. This unexpected observation was further supported by comparing the gene profiles of UCP1 KO and WT mice. Expression of key genes in glycolysis (enolase 1 and pyruvate kinase), thermogenesis (fatty acyl chain elongase and iodothyronine deiodinase 2), and myogenesis (Myod1 and myosin heavy chain 4) were upregulated at ambient temperature than at thermoneutrality (p < 0.01) in UCP1 KO mice.

Conclusions: Our results confirmed the presence of g-beige fat in SAT under thermal stress possibly mediated via activation of a myogenic state, without requiring UCP1. Uncovering the function of this newly discovered pathway in SAT may provide valuable insight into new targets for combating obesity and improving overall metabolic health.

Funding Sources: NIH R15AT008879-01A1