Objective: Monoacylglycerol O-acyltransferase 1 (Mogatl), a lipogenic enzyme that converts monoacylglycerol to diacylglycerol, is highly expressed in adipocytes and may regulate lipolysis by ...reesterifying fatty acids released during times when lipolytic rates are low. However, the role of Mogatl in regulating adipocyte fat storage during differentiation and diet-induced obesity is relatively understudied. Methods: Here, adipocyte-specific Mogatl knockout mice were generated and subjected to a high-fat diet to determine the effects of Mogatl deficiency on diet-induced obesity. Mogatl floxed mice were also used to develop preadipocyte cell lines wherein Mogatl could be conditionally knocked out to study adipocyte differentiation in vitro. Results: In preadipocytes, it was found that Mogatl knockout at the onset of preadipocyte differentiation prevented the accumulation of glycerolipids and reduced the differentiation capacity of preadipocytes. However, the loss of adipocyte Mogatl did not affect weight gain or fat mass induced by a high-fat diet in mice. Furthermore, loss of Mogatl in adipocytes did not affect plasma lipid or glucose concentrations or insulin tolerance. Conclusions: These data suggest Mogatl may play a role in adipocyte differentiation in vitro but not adipose tissue expansion in response to nutrient overload in mice.
The recent insight that brown adipocytes and muscle cells share a common origin and in this respect are distinct from white adipocytes has spurred questions concerning the origin and molecular ...characteristics of the UCP1-expressing cells observed in classic white adipose tissue depots under certain physiological or pharmacological conditions. Examining precursors from the purest white adipose tissue depot (epididymal), we report here that chronic treatment with the peroxisome proliferator-activated receptor γ agonist rosiglitazone promotes not only the expression of PGC-1α and mitochondriogenesis in these cells but also a norepinephrine-augmentable UCP1 gene expression in a significant subset of the cells, providing these cells with a genuine thermogenic capacity. However, although functional thermogenic genes are expressed, the cells are devoid of transcripts for the novel transcription factors now associated with classic brown adipocytes (Zic1, Lhx8, Meox2, and characteristically PRDM16) or for myocyte-associated genes (myogenin and myomirs (muscle-specific microRNAs)) and retain white fat characteristics such as Hoxc9 expression. Co-culture experiments verify that the UCP1-expressing cells are not proliferating classic brown adipocytes (adipomyocytes), and these cells therefore constitute a subset of adipocytes (“brite” adipocytes) with a developmental origin and molecular characteristics distinguishing them as a separate class of cells.
Obesity is a leading health problem facing the modern world; however, no effective therapy for this health issue has yet been developed. A promising research direction to identify novel therapies to ...prevent obesity has emerged from discoveries on development and function of brown/brite adipocytes in mammals. Importantly, there is evidence for the presence and function of active thermogenic brown adipocytes in both infants and adult humans. Several new investigations have shown that thermogenic adipocytes are beneficial to maintain glucose homeostasis, insulin sensitivity, and a healthy body fat content. Such thermogenic adipocytes have been considered as targets to develop a therapy for preventing obesity. This short review seeks to highlight recent findings on the development and function of brown/brite adipocytes in humans and to discuss potential treatments based on these adipocytes to reduce obesity and its related disorders.
To treat obesity, suppression of white adipose tissue (WAT) expansion and activation of brown adipose tissue (BAT) are considered as potential therapeutic targets. Recent advances have been made in ...the induction of brown fat-like adipocytes (beige) in WAT, which represents an attractive potential strategy for the management and treatment of obesity. Use of natural compounds for browning of white adipocytes can be considered as a safe and novel strategy against obesity. Here, we report that trans-anethole (TA), a flavoring substance present in the essential oils of various plants, alleviated high fat diet (HFD)-induced obesity in mice models via elevation of the expression of beige-specific genes such as Ppargc1α, Prdm16, Ucp1, Cd137, Cited1, Tbx1, and Tmem26. TA also regulated lipid metabolism in white adipocytes via reduction of adipogenesis and lipogenesis as well as elevation of lipolysis and fat oxidation. Moreover, TA exhibited thermogenic activity by increasing mitochondrial biogenesis in white adipocytes and activating brown adipocytes. In addition, molecular docking analysis enabled us to successfully predict core proteins for fat browning such as β3-adrenergic receptor (β3-AR) and sirtuin1 (SIRT1) based on their low binding energy interactions with TA for promotion of regulatory mechanisms. Indeed, agonistic and antagonistic studies demonstrated that TA induced browning of 3T3-L1 adipocytes through activation of β3-AR as well as the AMPK-mediated SIRT1 pathway regulating PPARα and PGC-1α. In conclusion, TA possesses potential therapeutic implications for treatment of obesity by playing multiple modulatory roles in the induction of white fat browning, activation of brown adipocytes, and promotion of lipid catabolism.
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•Trans-anethole (TA) regulates lipid metabolism in white adipocytes and induces browning.•TA reduces obesity by activating brown adipocytes.•TA demonstrates thermogenesis via increased mitochondrial biogenesis.•TA shows more effective binding with SIRT1 and follows a direct pathway of browning rather than β3-AR.
Adipose-derived stem cells (ADSCs) play critical roles in controlling obesity-associated inflammation and metabolic disorders. Exosomes from ADSCs exert protective effects in several diseases, but ...their roles in obesity and related pathological conditions remain unclear. In this study, we showed that treatment of obese mice with ADSC-derived exosomes facilitated their metabolic homeostasis, including improved insulin sensitivity (27.8% improvement), reduced obesity, and alleviated hepatic steatosis. ADSC-derived exosomes drove alternatively activated M2 macrophage polarization, inflammation reduction, and beiging in white adipose tissue (WAT) of diet-induced obese mice. Mechanistically, exosomes from ADSCs transferred into macrophages to induce anti-inflammatory M2 phenotypes through the transactivation of arginase-1 by exosome-carried active STAT3. Moreover, M2 macrophages induced by ADSC-derived exosomes not only expressed high levels of tyrosine hydroxylase responsible for catecholamine release, but also promoted ADSC proliferation and lactate production, thereby favoring WAT beiging and homeostasis in response to high-fat challenge. These findings delineate a novel exosome-mediated mechanism for ADSC-macrophage cross talk that facilitates immune and metabolic homeostasis in WAT, thus providing potential therapy for obesity and diabetes.
Brown adipose tissue (BAT) is a major site of nonshivering thermogenesis in mammals. Rodent studies indicated that BAT thermogenic activity may protect against obesity. Recent findings using novel ...radiodiagnosis procedures revealed unanticipated high activity of BAT in adult humans. Moreover, complex processes of cell differentiation leading to the appearance of active brown adipocytes have been recently identified. The brown adipocytes clustered in defined anatomical BAT depots of rodents arise from mesenchymal precursor cells common to the myogenic cell lineage. They are being called “classical” or “developmentally programmed” brown adipocytes. However, brown adipocytes may appear after thermogenic stimuli at anatomical sites corresponding to white adipose tissue (WAT). This process is called the “browning” of WAT. The brown adipocytes appearing in WAT derive from precursor cells different from those in classical BAT and are closer to the white adipocyte cell lineage. The brown adipocytes appearing in WAT are often called “inducible, beige, or brite.” The appearance of these inducible brown adipocytes in WAT may also involve transdifferentiation processes of white-to-brown adipose cells. There is no evidence that the ultimate thermogenic function of the beige/brite adipocytes differs from that of classical brown adipocytes, although some genetic data in rodents suggest a relevant role of the browning process in protection against obesity. Although the activation of classical BAT and the browning process share common mechanisms of induction (eg, noradrenergic-mediated induction by cold), multiple novel adrenergic-independent endocrine factors that activate BAT and the browning of WAT have been identified recently. In adult humans, BAT is mainly composed of beige/brite adipocytes, although recent data indicate the persistence of classical BAT at some anatomical sites. Understanding the biological processes controlling brown adipocyte activity and differentiation could help the design of BAT-focused strategies to increase energy expenditure and fight against obesity.
The ability to maintain and expand the pool of adipocytes in adults is integral to the regulation of energy balance, tissue/stem cell homeostasis, and disease pathogenesis. For decades, our knowledge ...of adipocyte precursors has relied on cellular models. The identity of native adipocyte precursors has remained unclear. Recent studies have identified distinct adipocyte precursor populations that are physiologically regulated and contribute to the development, maintenance, and expansion of adipocyte pools in mice. With new tools available, the properties of adipocyte precursors can now be defined, and the regulation and function of adipose plasticity in development and physiology can be explored.
Nutritional and pharmacological stimuli can dramatically alter the cellular phenotypes in white adipose tissue (WAT). Utilizing genetic lineage tracing techniques, we demonstrate that brown ...adipocytes (BA) that are induced by β3-adrenergic receptor activation in abdominal WAT arise from the proliferation and differentiation of cells expressing platelet-derived growth factor receptor alpha (PDGFRα), CD34, and Sca-1 (PDGFRα+ cells). PDGFRα+ cells have a unique morphology in which extended processes contact multiple cells in the tissue microenvironment. Surprisingly, these cells also give rise to white adipocytes (WA) that can comprise up to 25% of total fat cells in abdominal fat pads following 8 weeks of high-fat feeding. Isolated PDGFRα+ cells differentiated into both BA and WA in vitro and generated WA after transplantation in vivo. The identification of PDGFRα+ cells as bipotential adipocyte progenitors will enable further investigation of mechanisms that promote therapeutic cellular remodeling in adult WAT.
► β 3AR activation induces differentiation of PDGFRα+ cells into brown adipocytes ► Isolated PDGFRα+ cells have adipogenic potential in vivo and in vitro ► PDGFRα+ cells contribute to adipocyte hyperplasia induced by high-fat diet ► PDGFRα+ cells appear to be adult stem cells involved in WAT remodeling
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