Characterization of α-MSH browning effect in diverse mice white adipose tissue depots

White adipose tissue (WAT) browning is a potent mechanism to dissipate energy as heat and, thus, its activation constitutes a promise therapeutic approach to obesity. We previously reported the melanocortin α-melanocyte stimulating hormone (α-MSH) ability to increase the number of beige cells in subcutaneous inguinal WAT (ingWAT) in high fat diet (HFD)-fed mice. The current study examined the browning effect of intraperitoneally administered α-MSH on diverse fat depots from mice fed with HFD or standard rodent diet (SD). For this, mRNA expression of browning hallmark genes was quantified concomitantly with histological examination of the adipose tissue samples (epidydimal (eWAT), mesenteric (mWAT), retroperitoneal (rpWAT) or ingWAT). As well, α-MSH impact on body weight, serum profile, WAT mass and lipolytic rates were evaluated. In the visceral depots mWAT, eWAT and rpWAT from HFD-fed mice, α-MSH was not able to induce a browning mechanism. Surprisingly, in SD-fed mice, α-MSH decreased the expression of several beige-specific genes in rpWAT and promoted an increase of the size of lipid droplets. No browning effect was observed in ingWAT from SD-fed mice. We also verified that HFD ingestion per se stimulated the browning mechanisms in rpWAT, but not in mWAT and eWAT. In conclusion, the fat depots from diverse anatomical locations respond differently to α-MSH treatment when exposed to different diets.

Is Exercise a Match for Cold Exposure? Common Molecular Framework for Adipose Tissue Browning

Exercise is commonly utilized for weight loss, yet research has focused less on specific modifications to adipose tissue metabolism. White adipose tissue (WAT) is the storage form of fat, whereas brown adipose tissue (BAT) is a thermogenic tissue whose uncoupling increases energy expenditure. The most established BAT activator is cold exposure, which also transforms WAT into “beige cells” that express uncoupling protein 1 (UCP1). Preliminary evidence in rodents suggests exercise elicits similar effects. The purpose of this review is to parallel and examine differences between exercise and cold exposure on BAT activation and beige induction. Like cold exposure, exercise stimulates the sympathetic nervous system and activates molecular pathways responsible for BAT/beige activation, including upregulation of BAT activation markers (UCP1, proliferator-activated receptor-gamma coactivator-1α) and stimulation of endocrine activators (fibroblast growth factor-21, irisin, and natriuretic peptides). Further, certain BAT activators are altered exclusively by exercise (interleukin-6, lactate). Markers of BAT activation increase from both cold exposure and exercise, whereas effects in WAT are compartment-specific. Stimulation of endocrine activators depends on numerous factors, including stimulus intensity and duration. Evidence of these analogous, albeit not mirrored, mechanisms is demonstrated by increases in adipose activity in rodents, while effects remain challenging to quantify in humans.

Role of small proliferative adipocytes: possible beige cell progenitors

Despite extensive investigation, the mechanisms underlying adipogenesis are not fully understood. We previously identified proliferative cells in adipose tissue expressing adipocyte-specific genes, which were named small proliferative adipocytes (SPA). In this study, we investigated the characteristics and roles of SPA in adipose tissue. Epididymal and inguinal fat was digested by collagenase, and then SPA were separated by centrifugation from stromal vascular cells (SVC) and mature white adipocytes. To clarify the feature of gene expression in SPA, microarray and real-time PCR were performed. The expression of adipocyte-specific genes and several neuronal genes was increased in the order of SVC < SPA < mature white adipocytes. In addition, proliferin was detected only in SPA. SPA differentiated more effectively into lipid-laden cells than SVC. Moreover, differentiated SPA expressed uncoupling protein 1 and mitochondria-related genes more than differentiated SVC. Treatment of SPA with pioglitazone and CL316243, a specific β3-adrenergic receptor agonist, differentiated SPA into beige-like cells. Therefore, SPA are able to differentiate into beige cells. SPA isolated from epididymal fat (epididymal SPA), but not SPA from inguinal fat (inguinal SPA), expressed a marker of visceral adipocyte precursor, WT1. However, no significant differences were detected in the expression levels of adipocyte-specific genes or neuronal genes between epididymal and inguinal SPA. The ability to differentiate into lipid-laden cells in epididymal SPA was a little superior to that in inguinal SPA, whereas the ability to differentiate into beige-like cells was greater in inguinal SPA than epididymal SPA. In conclusion, SPA may be progenitors of beige cells.

Effects of royal jelly and tocotrienol rich fraction in obesity treatment of calorie-restricted obese rats: a focus on white fat browning properties and thermogenic capacity

Background: Obesity has reached an alarming rate worldwide. Promoting thermogenesis via increasing brown adipose tissue (BAT) function or white adipose tissue (WAT) browning has been propounded as a new approach to fight against obesity. The goal of the study was to evaluate the effect of Royal Jelly (RJ) and tocotrienol rich fraction (TRF) on BAT activation and WAT browning during calorie restriction diet (CRD) in obesity model. Methods: In this experimental study 50 obese Wistar rats were randomly divided into 5 groups and received one of the following treatments for 8 weeks: High-fat diet (HFD), CRD, RJ+CRD, TRF+CRD, RJ+TRF+CRD. Effects of RJ and TRF, individually and their combination on body weight and the expression of key thermoregulatory genes in WAT, BAT were examined by quantitative real-time (qRT-PCR). Morphological alterations were assessed by hematoxylin and eosin staining. Results: RJ (-67.21g ±4.84g) and RJ+TRF (-73.29g ±4.51g) significantly reduced weight gain relative to the CRD group (-40.70g ±6.50g, P<0.001). Compared with the CRD group, RJ and RJ+TRF remarkably enhanced the uncoupling protein1 (UCP1) expression in WAT (5.81, 4.72 fold, P<0.001) and BAT (4.99, 4.75 fold, P<0.001). The expression of PR domain containing 16(PRDM 16), cAMP response element-binding protein1 (CREB1), P38 mitogen-activated protein kinases (P38MAPK), Bone morphogenetic protein8B (BMP8B) increased significantly following RJ and RJ+TRF treatment (P<0.001).However, the expression levels of CCAAT/enhancer-binding protein beta (CEBPβ) and Bone morphogenetic protein7 (BMP7) did not change remarkably. Multilocular beige cells in WAT and compacted dense adipocytes in BAT of RJ and RJ+TRF received groups were observed. TRF did not demonstrate substantial effects on the expression of mentioned thermoregulatory genes and brown fat-like phenotype. Conclusion: Our results suggest that Royal Jelly promotes thermogenesis and browning of WAT, contributing to an increase in energy expenditure. Thus, Royal Jelly may give rise to a novel dietary choice to attenuate obesity.

Beige Fat, Adaptive Thermogenesis, and Its Regulation by Exercise and Thyroid Hormone

While it is now understood that the proper expansion of adipose tissue is critically important for metabolic homeostasis, it is also appreciated that adipose tissues perform far more functions than simply maintaining energy balance. Adipose tissue performs endocrine functions, secreting hormones or adipokines that affect the regulation of extra-adipose tissues, and, under certain conditions, can also be major contributors to energy expenditure and the systemic metabolic rate via the activation of thermogenesis. Adipose thermogenesis takes place in brown and beige adipocytes. While brown adipocytes have been relatively well studied, the study of beige adipocytes has only recently become an area of considerable exploration. Numerous suggestions have been made that beige adipocytes can elicit beneficial metabolic effects on body weight, insulin sensitivity, and lipid levels. However, the potential impact of beige adipocyte thermogenesis on systemic metabolism is not yet clear and an understanding of beige adipocyte development and regulation is also limited. This review will highlight our current understanding of beige adipocytes and select factors that have been reported to elicit the development and activation of thermogenesis in beige cells, with a focus on factors that may represent a link between exercise and ‘beiging’, as well as the role that thyroid hormone signaling plays in beige adipocyte regulation.

Berberine Promotes Beige Adipogenic Signatures of 3T3-L1 Cells by Regulating Post-transcriptional Events

Induced brown adipocytes (also referred to as beige cells) execute thermogenesis, as do the classical adipocytes by consuming stored lipids, being related to metabolic homeostasis. Treatment of phytochemicals, including berberine (BBR), was reported to induce conversion from white adipocytes to beige cells. In this study, results of microRNA (miRNA)-seq analyses revealed a decrease in miR-92a, of which the transcription is driven by the c13orf25 promoter in BBR-treated 3T3-L1 cells. BBR treatment manipulated the expressions of SP1 and MYC, in turn, reducing the activity of the c13orf25 promoter. A decrease in miR-92a led to an increase in RNA-binding motif protein 4a (RBM4a) expression, which facilitated the beige adipogenesis. Overexpression of miR-92a or depletion of RBM4a reversely interfered with the impact of BBR treatment on the beige adipogenic signatures, gene expressions, and splicing events in 3T3-L1 cells. Our findings demonstrated that BBR treatment enhanced beige adipogenesis of 3T3-L1 cells through transcription-coupled post-transcriptional regulation.

The β3-adrenergic receptor is dispensable for browning of adipose tissues

Brown and brite/beige adipocytes are attractive therapeutic targets to treat metabolic diseases. To maximally utilize their functional potential, further understanding is required about their identities and their functional differences. Recent studies with β3-adrenergic receptor knockout mice reported that brite/beige adipocytes, but not classical brown adipocytes, require the β3-adrenergic receptor for cold-induced transcriptional activation of thermogenic genes. We aimed to further characterize this requirement of the β3-adrenergic receptor as a functional distinction between classical brown and brite/beige adipocytes. However, when comparing wild-type and β3-adrenergic receptor knockout mice, we observed no differences in cold-induced thermogenic gene expression ( Ucp1, Pgc1a, Dio2, and Cidea) in brown or white (brite/beige) adipose tissues. Irrespective of the duration of the cold exposure or the sex of the mice, we observed no effect of the absence of the β3-adrenergic receptor. Experiments with the β3-adrenergic receptor agonist CL-316,243 verified the functional absence of β3-adrenergic signaling in these knockout mice. The β3-adrenergic receptor knockout model in the present study was maintained on a FVB/N background, whereas earlier reports used C57BL/6 and 129Sv mice. Thus our data imply background-dependent differences in adrenergic signaling mechanisms in response to cold exposure. Nonetheless, the present data indicate that the β3-adrenergic receptor is dispensable for cold-induced transcriptional activation in both classical brown and, as opposed to earlier studies, brite/beige cells.