CL316,243 and skeletal muscle metabolism: role of sex and estrogen receptor beta.

CL316,243 (CL), a beta 3 adrenergic receptor (B3-AR) agonist, has 'exercise mimetic' effects in adipose tissue. CL may also positively affect skeletal muscle (SM), yet the role of estrogen receptor beta (ERβ) in mediating SM-specific effects of CL is not known. We investigated the effects of CL on SM metabolism, as well as the role played by ERβ. High-fat diet-fed male and female wild-type (WT) and ERβ DBD knockout (KO) mice were administered CL daily for 2 weeks. Quadriceps SM protein markers of fatty acid oxidation (FatOx), protein synthesis, and protein catabolism were assessed. CL increased relative lean mass in both sexes (P = 0.012). In females, CL increased FatOx in WT, yet reduced FatOx in KO, while among males, CL reduced FatOx independent of genotype (P = 0.04). Uncoupling protein 2 (UCP2) and fatty acid synthase (FASN) abundance were higher in females (P = 0.004 and 0.037, respectively), and in both sexes, KO mice had higher SM UCP2 abundance (P = 0.022). CL increased phosphorylated acetyl-CoA carboxylase in males, yet reduced it in females (P = 0.015). Similarly, CL affected p706S kinase abundance (indicative of anabolic signaling) in a sexually dimorphic manner, increasing in males and decreasing in females. CL robustly increased SM FASN across sexes and genotypes (P < 0.001). In summary, the most salient finding was that CL increased SM FASN content independent of sex and ERβ genomic activity; additional novel sex-divergent effects of CL on SM metabolism were identified, some of which were affected by ERβ genomic activity.