Genistein Stimulation of White Adipose Tissue Thermogenesis Is Partially Dependent on GPR30 in Mice

Abstract

Scope: Genistein increases whole body energy expenditure by stimulating white adipose tissue (WAT) browning and thermogenesis. G-Coupled receptor GPR30 can mediate some actions of genistein, however, it is not known whether it is involved in the activation of WAT-thermogenesis. Thus, the aim of the study is to determine whether genistein activates thermogenesis coupled to an increase in WAT browning and mitochondrial activity, in GPR30 +/+ and GPR30 −/− mice. Methods and Results: GPR30 +/+ and GPR30 −/− mice are fed control or high fat sucrose diets containing or not genistein for 8 weeks. Body weight and composition, energy expenditure, glucose tolerance, and browning markers in WAT, and oxygen consumption rate, 3', 5'-cyclic adenosine monophosphate (cAMP) concentration and browning markers in adipocytes are evaluated. Genistein consumption reduces body weight and fat mass gain in a different extent in both genotypes, however, energy expenditure is lower in GPR30 −/− compared to GPR30 +/+ mice, accompanied by a reduction in browning markers, maximal mitochondrial respiration, cAMP concentration, and browning markers in cultured adipocytes from GPR30 −/− mice. Genistein improves glucose tolerance in GPR30 +/+ , but this is partially observed in GPR30 −/− mice. Conclusion: The results show that GPR30 partially mediates genistein stimulation of WAT thermogenesis and the improvement of glucose tolerance.

Deletion of GPR30 Drives the Activation of Mitochondrial Uncoupling Respiration to Induce Adipose Thermogenesis in Female Mice

“…In contrast to our previous finding that deletion of GPR30 only exerted metabolic effects in female but not male mice fed either a high fat diet or chow diet ( 24 ), a recent study reported that isoflavone genistein, a GPR30 agonist, increased adipose cAMP content, UCP-1 expression, and energy expenditure while reducing body weight and fat mass gain in wild-type male mice, but these effects were blunted in GPR30 -/- mice ( 64 ), suggesting that activation of GPR30 promotes thermogenic program in adipose tissue in male mice. These observations also contradict to our findings in the present study that inactivation of GPR30 increased cAMP production and thermogenic adipocyte differentiation in female mice.…”

Genistein‐mediated thermogenesis and white‐to‐beige adipocyte differentiation involve transcriptional activation of cAMP response elements in the Ucp1 promoter

“…On the contrary, it has been shown that an increase in the concentration of cAMP stimulated by genistein is required to activate Ucp1 gene transcription, suggesting that genistein may promote its expression via PKA/CREB. Recent evidence has demonstrated that the increase of cAMP is in part mediated by the interaction of genistein with the GPR30 receptor 23 . The in silico analysis showed the presence of four putative CREs as previously described by Kozak and coworkers 32 .…”

“…Additionally, some studies have shown evidence that genistein can activate thermogenesis by increasing the browning process in WAT, an effect associated with an increase in UCP1. 17,23 In the present study, we demonstrated that genistein administration reduced scWAT and eWAT adipocyte size and induced Ucp1 expression at thermoneutrality. This result indicated that this effect could be independent of cold-activated sympathetic activity, revealing a new genistein-mediated browning remodeling model that reinforced our previous studies.…”

“…Recent evidence has demonstrated that the increase of cAMP is in part mediated by the interaction of genistein with the GPR30 receptor. 23 The in silico analysis showed the presence of four putative CREs as previously described by Kozak and coworkers. 32 To establish if a cAMPresponsive element was involved in the mechanism by which genistein activates Ucp1 transcription, we incubated the cells with H89, or MDL-12330A, inhibitors of PKA and adenylate cyclase, respectively.…”

“…Intraperitoneal administration of genistein in Wistar rats increases the expression of the peroxisome proliferator‐activated receptor γ co‐activator 1 α (PGC‐1α) and UCP1, as well as some other browning markers in subcutaneous WAT (scWAT) 17 . It is noteworthy to mention that genistein also increases intracellular concentrations of cAMP in muscle and adipose tissue 17,22 and more recently, in differentiated adipocytes 23 suggesting the participation of the cAMP/PKA/CREB pathway. However, the link between this activation and the induction of the thermogenic program in WAT is still unknown.…”