Guggulsterone Activates Adipocyte Beiging through Direct Effects on 3T3-L1 Adipocytes and Indirect Effects Mediated through RAW264.7 Macrophages

Abstract

Background: Plant-derived phytochemicals have been of emerging interest as anti-obesity compounds due to their apparent effects on promoting reduced lipid accumulation in adipocytes. Despite such promising evidence, little is known about the potential mechanisms behind their anti-obesity effects. The aim of this study is to establish potential anti-obesity effects of the phytochemical guggulsterone (GS). Methods: Mature 3T3-L1 adipocytes were treated with GS, derived from the guggul plant native in northern India, to investigate its effects on mitochondrial biogenesis and adipocyte “beiging.” Further, to explore the relationship between macrophages and adipocytes, 3T3-L1s were treated with conditioned media from GS-treated RAW264.7 macrophages. Markers of mitochondrial biogenesis and beiging were measured by western blot. Results: GS treatment in adipocytes resulted in increased mitochondrial density, biogenesis (PGC1α and PPARγ), and increased markers of a beige adipocyte phenotype (UCP1, TBX1, and β-3AR). This upregulation in mitochondrial expression was accompanied by increases oxygen consumption. In GS-treated macrophages, markers of M2 polarization were elevated (e.g., arginase and IL-10), along with increased catecholamine release into the media. Lastly, 3T3-L1 adipocytes treated with conditioned media from macrophages induced a 167.8% increase in UCP1 expression, suggestive of a role of macrophages in eliciting an anti-adipogenic response to GS. Conclusions: Results from this study provide the first mechanistic understanding of the anti-obesity effects of GS and suggests a role for both direct GS-signaling and indirect stimulation of M2 macrophage polarization in this model.

Commiphora myrrha Resin Alcoholic Extract Ameliorates High Fat Diet Induced Obesity via Regulation of UCP1 and Adiponectin Proteins Expression in Rats

“…Moreover, it up-regulates the expression of a thermogenic marker, UCP1, in mature adipocytes. The hypocholestermic effect of CME may be related to the inhibition of cholesterol synthesis via antagonism of foresenoid X receptor and bile receptor [60] as Guggulsterone is structurally similar to bile acids [61] and through its effect on UCP1 expression. Thus, Guggulsterone acts as anti-obesity agent via reducing adipogenesis, increasing lipolysis in white adipose tissue and inducing trans-differentiation of white adipocytes into beige that decrease body weight.…”

Therapeutic Effect of Guggulsterone in Primary Cultured Orbital Fibroblasts Obtained From Patients with Graves’ Orbitopathy

“…11 Recently, it was reported that GS treatment in 3T3-L1 adipocytes increased mitochondrial density and markers of the brown adipocyte phenotype, such as UCP1. 12 GS is the only known farnesoid X receptor (FXR) antagonist, a bile acid receptor expressed in adult mouse white adipose tissue and differentiated 3T3-L1 cells. 44 In a study by Rizzo et al, 44 a potent and selective FXR ligand increased 3T3-L1 differentiation, which was reversed by GS.…”

“…Additionally, several studies have shown that GS inhibits adipocyte differentiation, induces lipolysis in mature adipocytes, 11 suppresses LDL oxidation, 9 and activates adipocyte beiging. 12 Here we aimed to explore the potential regulatory effect of GS with regard to the main pathological events of GO in primary cultures of orbital fibroblasts from GO patients.…”

Lipocalin-2 deficiency may predispose to the progression of spontaneous age-related adiposity in mice

“…3T3-L1 cells at passage numbers between 6 and 15 were used and the differentiation potential of the cells was determined by the morphological changes and lipid deposition after the induction of differentiation process where preadipocytes develop into mature adipocytes. Differentiation of 3T3-L1 preadipocytes was carried out as we previously described 71,72 . Briefly, 3T3-L1 preadipocytes were cultured in medium containing Dulbecco's Modified Eagle Medium (DMEM) GlutaMAX with 10% calf serum and 1% penicillin-streptomycin.…”