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Myf5-lineage adipocytes express lower levels BAT genes and beige cell markers than the non-Myf5- + Ϫ + + Ϫ Ϫ lineage cells within the same SAT depot. (A, B) Four populations (Sca1 Myf5 , Sca1 Myf5 , Sca1 Myf5 , Ϫ + Sca1 Myf5 ) were isolated by FACS from the asWAT SVF cells of Myf5-Cre/Rosa26-tdTomato mice using RFP
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Brown adipose tissues (BAT) are derived from a Myf5-expressing cell lineage and white adipose tissues (WAT) predominantly arise from non-Myf5 lineages, though a subpopulation of adipocytes in some WAT depots can be derived from the Myf5-lineage. However, the functional implication of the Myf5 and non-Myf5 lineage cells in WAT is unclear. We found t...
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... investigate the progeny of Myf5-lineage cells in various tissues, we conducted lineage-tracing experiments using Myf5-Cre driver and Rosa26-tdTomto reporter mice ( 29, 30 ), in which Myf5-lineage cells were labeled by tdTomato, an improved RFP. Consistent with previous reports ( 15 ), the vast majority of cells in muscle and BAT cross-sections were RFP-positive (supplementary Fig. I, A, B), suggesting that the Myf5 lineage contributes to these tissues. This observation also demonstrates the effectiveness of our lineage tracing model. RFP-positive cells were also detected in the heart, brain, and spleen, but not in the liver, lung, or kidney (supplementary Fig. I, C–H). Importantly, RFP-positive cells can be detected in depots of the asWAT, ingWAT, and eWAT (supplementary Fig. I, I–K). Costaining with adipocyte marker aP2 confi rmed that the RFP-positive cells in these adipose depots are bona fi de adipocytes (supplementary Fig. I, L–N). These results demonstrate that a subpopulation of adipocytes in various WAT depots is derived from the Myf5-lineage progenitors. To further characterize whether the Myf5 lineage gives rise to adipose progenitors in WAT, we isolated the SVF cells and found RFP-positive cells in the SVF cells ( Fig. 1A –C ). Quantitative analysis indicated that there are about 31, 11, and 14% RFP-positive cells in the SVF of asWAT, ingWAT, and eWAT, respectively ( Fig. 1D–F ). To examine whether at least some of the RFP-positive SVF cells are adipogenic progenitors, we fi rst examined the expression of Sca1, an established marker for adipose stem cells ( 31, 32 ). FACS analysis (refer to Fig. 3 for details) indicated that 13, 4, and 4% of freshly isolated Lin-negative SVF cells in asWAT, ingWAT, and eWAT were double-positive + + for RFP Sca1 , respectively (supplementary Fig. II). We next induced the SVF cells to undergo adipogenic differentiation. After induction and differentiation, about 45% and 6% of mature adipocytes were RFP-positive in the asWAT ( Fig. 2A , B ) and ingWAT ( Fig. 2C, D ), indicating that Myf5-lineage SVF cells have the adipogenic differentiation potential in vitro. Together, these results suggest that a subpopulation of WAT adipocytes and SVF cells are derived from Myf5-lineage precursors. Given that BAT adipocytes are derived from the Myf5 lineage ( 15 ), we hypothesized that Myf5-lineage adipocytes in WAT should express higher levels of BAT and beige signature genes. To test this hypothesis, we fi rst examined whether the relative abundance of Myf5-lineage adipocytes in different WAT depots affects the expression of BAT signature genes, including Ucp1 , Prdm16 , Cidea , and Ppargc1a . Contrary to what we expected, we found that the abundance of RFP-positive adipocytes in the asWAT and ingWAT was inversely correlated to the mRNA levels of the BAT marker genes ( Fig. 2E, F ). Likewise, the expression level of beige adipocyte markers Tmem26 and Tbx1 was inversely correlated to the abundance of RFP-positive adipocytes in the asWAT and ingWAT ( Fig. 2G ). The inverse correlation between the abundance of Myf5-lineage adipocytes and BAT/beige gene expression in different WAT depots may be due to depot-specifi c differences other than Myf5-lineage contribution. To address this possibility, we examined whether Myf5-lineage and non-Myf5-lineage adipocytes within the same WAT depot expressed different levels of BAT/beige marker genes. We purifi ed four populations from the asWAT by FACS + + + Ϫ Ϫ + Ϫ Ϫ (RFP Sca1 , RFP Sca1 , RFP Sca1 , and RFP Sca1 ; all Ϫ Lin ) of SVF cells ( Fig. 3A , B ). We then induced them to undergo adipogenic differentiation and examined the expression of BAT/beige markers in the differentiated adipocytes. Only Sca1-positive cells had adipogenic potential, Ϫ + + + and the RFP Sca1 and RFP Sca1 cells had similar adipogenic potency ( Fig. 3C, D ), as is also evident from their identical expression levels of Adipoq and Leptin (Refer to + Ϫ Fig. 3G ). Interestingly, the RFP Sca1 cells gave rise to numerous myotubes after differentiation under adipogenic Ϫ Ϫ conditions ( Fig. 3F ), whereas the RFP Sca1 cells failed to form adipocytes or myotubes ( Fig. 3E ). Consistent with our + + earlier observations, the RFP Sca1 SVF gave rise to adipocytes expressing signifi cantly lower levels of BAT marker genes Ucp1 , Prdm16 , Cidea , and Ppargc1a compared with the Ϫ + RFP Sca1 descendant adipocytes ( Fig. 3G ). Additionally, + + the RFP Sca1 -descendant adipocytes expressed signifi cantly lower levels of beige marker genes CD137 , Tmem26 , Ϫ + and Tbx1 compared with the RFP Sca1 -derived adipocytes ( Fig. 3H ). Similar BAT/beige marker expression pat- terns were observed in Myf5-lineage and non-Myf5-lineage adipocytes derived from ingWAT (supplementary Fig. III, A–D). Together, these data provide compelling evidence that the Myf5-lineage adipocytes are less brown than the non-Myf5-lineage adipocytes within the same WAT depot. To further confi rm these results, we established the Myf5-Cre/Rosa26-iDTR mouse model ( 17, 33 ). In this model, Myf5-Cre induces the expression of DT receptor (DTR), which is normally not expressed by murine cells, and ren- ders the Myf5-lineage cells sensitive to DT. Thus, DT treatment should selectively ablate all Myf5-lineage cells but not the non-Myf5-lineage cells. SVF cells cultured from Myf5-Cre/Rosa26-iDTR mice were treated with DT to ablate the Myf5-lineage cells, then grown to confl uence and induced to undergo adipogenic differentiation. Ablation of Myf5-lineage SVF cells did not affect the accumulation of lipids and the expression of the mature adipocyte markers Adipoq and Leptin , but it signifi cantly upregulated the mRNA levels of BAT markers Ucp1 , Prdm16 , Cidea , Ppargc1a , and Ppara ( Fig. 3I ). The beige cell markers Tmem26 and Tbx1 were also increased signifi cantly after ablation of Myf5-lineage SVF cells ( Fig. 3J ). Taken together, the inter- depot comparison, intradepot analysis of Myf5-lineage and non-Myf5-lineage adipocytes and lineage ablation studies demonstrate that Myf5-lineage adipocytes express lower levels of brown and beige adipocyte markers than the non- Myf5-lineage adipocytes. Adipose-derived stem cells have the potential to differentiate into multiple lineages, including adipogenic, chon- drogenic, and myogenic differentiations ( 23 ). Our FACS analysis demonstrated that the adipogenic and myogenic activities were not shared by a common stem cell population but rather resided in distinct progenitor cell populations ( Fig. 3C–F ). We attempted to further examine the lineage origin of myogenic ...
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... BAT and skeletal muscle have shared metabolic features and embryonic origins. Genetic fate mapping experiments in mice demonstrate that the dermomyotome regions of the somites, marked by the expression of transcription factors including Pax3, Pax7, Meox1, and Myf5, gives rises to most fat cells within the interscapular and retroperitoneal adipose depots [15][16][17][18][19][20]. The fact that these lineages trace to dorsal-anterior-located muscle, brown and white adipocytes suggests that they are location markers, rather than identity markers. ...
Brown adipose tissue (BAT) dissipates energy as heat, contributing to temperature control, energy expenditure, and systemic homeostasis. In adult humans, BAT mainly exists in supraclavicular areas and its prevalence is associated with cardiometabolic health. However, the developmental origin of supraclavicular BAT remains unknown. Here, using genetic cell marking in mice, we demonstrate that supraclavicular brown adipocytes do not develop from the Pax3 ⁺ / Myf5 ⁺ epaxial dermomyotome that gives rises to interscapular BAT (iBAT). Instead, the Tbx1 ⁺ lineage that specifies the pharyngeal mesoderm marks the majority of supraclavicular brown adipocytes. Tbx1 Cre -mediated ablation of peroxisome proliferator-activated receptor gamma (PPARγ) or PR/SET Domain 16 (PRDM16), components of the transcriptional complex for brown fat determination, leads to supraclavicular BAT paucity or dysfunction, thus rendering mice more sensitive to cold exposure. Moreover, human deep neck BAT expresses higher levels of the TBX1 gene than subcutaneous neck white adipocytes. Taken together, our observations reveal location-specific developmental origins of BAT depots and call attention to Tbx1 ⁺ lineage cells when investigating human relevant supraclavicular BAT.
... Classical BAs are derived from a population of progenitor cells predominantly expressing myogenic factor 5 (Myf5) [10][11][12]. During embryogenesis, these progenitor cells invade BAT preadipocytes and then differentiate into mature BAs [13]. ...
... We hypothesize that their observations are inconsistent because Ap2-Cre primarily mediates the knockdown or knockout of mature adipocytes [44,45]. BAT is primarily derived from an Myf5-positive lineage [11,32,46], which mediated the deletion of genes in BAT and skeletal muscle progenitors during embryonic development. These findings suggest that the Cre sources may lead to different BAT phenotypes after Sufu elimination. ...
Brown adipose tissue (BAT) is the major site of non-shivering thermogenesis and crucial for systemic metabolism. Under chronic cold exposures and high-fat diet challenges, BAT undergoes robust remodeling to adapt to physiological demands. However, whether and how BAT regenerates after acute injuries are poorly understood. Here, we established a novel BAT injury and regeneration model (BAT-IR) in mice and performed single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq to determine cellular and transcriptomic dynamics during BAT-IR. We further defined distinct fibro-adipogenic and myeloid progenitor populations contributing to BAT regeneration. Cell trajectory and gene expression analyses uncovered the involvement of MAPK, Wnt, and Hedgehog (Hh) signaling pathways in BAT regeneration. We confirmed the role of Hh signaling in BAT development through Myf5 Cre - mediated conditional knockout (cKO) of the Sufu gene to activate Hh signaling in BAT and muscle progenitors. Our BAT-IR model therefore provides a paradigm to identify conserved cellular and molecular mechanisms underlying BAT development and remodeling.
... Brown and beige adipocytes are functionally the same, but their origins differ. Beige and white adipocytes are mostly Myf5 negative (9)(10)(11), while brown adipocytes are Myf5 positive and share a precursor cell with myocyte (12). Prdm16 is the master gene for brown and beige adipocyte identity. ...
An energy imbalance cause obesity: more energy intake or less energy expenditure, or both. Obesity could be the origin of many metabolic disorders, such as type 2 diabetes and cardiovascular disease. UCP1 (uncoupling protein1), which is highly and exclusively expressed in the thermogenic adipocytes, including beige and brown adipocytes, can dissipate proton motive force into heat without producing ATP to increase energy expenditure. It is an attractive strategy to combat obesity and its related metabolic disorders by increasing non-shivering adipocyte thermogenesis. Adipocyte thermogenesis has recently been reported to be regulated by several new genes. This work provided novel and potential targets to activate adipocyte thermogenesis and resist obesity, such as secreted proteins ADISSP and EMC10, enzyme SSU72, etc. In this review, we have summarized the latest research on adipocyte thermogenesis regulation to shed more light on this topic.
... Instead of ATP synthesis, this process converts transmembrane potential into heat production [33]. Beige adipocytes residing in WAT originate from the same mesenchymal lineage as WAT, yet harbor a similar phenotype to BAT, possess multilocular lipid droplets, and abundant mitochondria capable of thermogenesis [34]. Several external stimuli such as cold exposure [35], adrenergic stimulation [36], and nutritional manipulation or pharmacological treatments [37,38], have been demonstrated to induce biogenesis and thermogenesis in beige adipocytes, leading to increased heat production and energy expenditure. ...
... A transcriptional complex composed of BMP-7 signals, PR domain containing 16 as well as CCAAT/ enhancer-binding protein (C/EBP) beta drives Myf5 + precursors into a thermogenic program with co-activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) and PPAR-γ co-activator 1 alpha (PGC-1α), facilitating the formation of brown adipocytes. Partial Myf5progenitors also undergo a thermogenic process, but they transform into beige-adipocytes with specific genes expression like CD137, transmembrane protein 26, and T-box 1 [34]. The other Myf5population turns into white pre-adipocytes through BMP2 and BMP4 signaling [42]. ...
Pancreatic cancer (PC) remains one of the most lethal malignancies across the world, which is due to delayed diagnosis and resistance to current therapies. The interactions between pancreatic tumor cells and their tumor microenvironment (TME) allow cancer cells to escape from anti-cancer therapies, leading to difficulties in treating PC. With endocrine function and lipid storage capacity, adipose tissue can maintain energy homeostasis. Direct or indirect interaction between adipocytes and PC cells leads to adipocyte dysfunction characterized by morphological change, fat loss, abnormal adipokine secretion, and fibroblast-like transformation. Various adipokines released from dysfunctional adipocytes have been reported to promote proliferation, invasion, metastasis, stemness, and chemoresistance of PC cells via different mechanisms. Additional lipid outflow from adipocytes can be taken into the TME and thus alter the metabolism in PC cells and surrounding stromal cells. Besides, the trans-differentiation potential enables adipocytes to turn into various cell types, which may give rise to an inflammatory response as well as extracellular matrix reorganization to modulate tumor burden. Understanding the molecular basis behind the protumor functions of adipocytes in PC may offer new therapeutic targets.
... mtRNA-induced Ifnb expression. Interscapular brown adipocytes are strongly thermogenic cells and are descendants of the Myf5 + lineage derived from skeletal muscle progenitors in mice [78][79][80] . Primates and humans have different thermoregulatory mechanisms than those of small rodents 17 , and thermogenic adipocytes of a newborn human are scattered within white fat depots 12 . ...
... Equivalents of these cells appear in newborn mice as well 11 . These thermogenic fat cells are unrelated to Myf5 + progenitors, and they develop from progenitors of white fat cells 79 . It appears that thermogenic fat cells in newborn subcutaneous tissue and in adult interscapular adipose tissue have distinct transcriptional profiles and specific developmental programmes 11,81 . ...
Childhood obesity is a serious public health crisis and a critical factor that determines future obesity prevalence. Signals affecting adipocyte development in early postnatal life have a strong potential to trigger childhood obesity; however, these signals are still poorly understood. We show here that mitochondrial (mt)RNA efflux stimulates transcription of nuclear-encoded genes for mitobiogenesis and thermogenesis in adipocytes of young mice and human infants. While cytosolic mtRNA is a potential trigger of the interferon (IFN) response, young adipocytes lack such a response to cytosolic mtRNA due to the suppression of IFN regulatory factor (IRF)7 expression by vitamin D receptor signalling. Adult and obese adipocytes, however, strongly express IRF7 and mount an IFN response to cytosolic mtRNA. In turn, suppressing IRF7 expression in adult adipocytes restores mtRNA-induced mitobiogenesis and thermogenesis and eventually mitigates obesity. Retrograde mitochondrion-to-nucleus signalling by mtRNA is thus a mechanism to evoke thermogenic potential during early adipocyte development and to protect against obesity.
... ECs, fibroblasts, macrophages, immune cells, and pre-adipocytes (generally referred to as the stromal vascular fraction, SVF) are also present. White adipocytes derive from myogenic factor 5 (Myf5)cells upon the increase in the expression of BMP2/4, peroxisome proliferator-activated receptor-ɣ (PPARɣ), and CEBPα/β/δ and in part from the Myf5 + mesenchymal stem cells that lose the expression of PTEN and activate the expression of PPARɣ and CEBPα/β/δ [96][97][98]. However, Myf5 lineage distribution in adipose tissues changes in response to both non-modifiable (e.g., age) and modifiable (e.g., diet) factors, suggesting that adipocyte lineages could have context-dependent plasticity [99]. ...
... In adults, small and metabolically active depots of BAT have been documented in the cervical, supraclavicular, axillary, periaortic, paravertebral, and suprarenal regions [101,102]. Brown adipocytes derive from Myf5 + mesenchymal precursor cells which start expressing BMP7, PMDR16 followed by PPARɣ, CEBPα/β/δ, and PGC-1α [96,97,99,103]. Brown adipocytes contain multiple, small LDs and a high number of mitochondria expressing the uncoupling protein 1 (UCP1), also known as thermogenin. UCP1 is a fatty acid anion/H + symporter located in the inner membrane of mitochondria whose main role is to dissipate the proton gradient generated by the electron transport chain. ...
... The plasticity of the adipose organ is well documented by the ability of adipocytes to undergo specific morphofunctional modifications to respond to diverse stimuli. The phenomenon of browning, occurring in specific white adipose depots, consists of the differentiation of adipocytes progenitors in brown adipocytes [97] and of the transdifferentiation of white adipocytes into brown-like cells (beige) upon cold-exposure [106]. Such ability holds critical implication in the formulation of therapies to counteract obesity. ...
Gremlin-1 is a secreted bone morphogenetic protein (BMP) antagonist playing a pivotal role in the regulation of tissue formation and embryonic development. Since its first identification in 1997, gremlin-1 has been shown to be a multifunctional factor involved in wound healing, inflammation, cancer and tissue fibrosis. Among others, the activity of gremlin-1 is mediated by its interaction with BMPs or with membrane receptors such as the vascular endothelial growth factor receptor 2 (VEGFR2) or heparan sulfate proteoglycans (HSPGs). Growing evidence has highlighted a central role of gremlin-1 in the homeostasis of the adipose tissue (AT). Of note, gremlin-1 is involved in AT dysfunction during type 2 diabetes, obesity and non-alcoholic fatty liver disease (NAFLD) metabolic disorders. In this review we discuss recent findings on gremlin-1 involvement in AT biology, with particular attention to its role in metabolic diseases, to highlight its potential as a prognostic marker and therapeutic target.
... The Myf5 + progenitor cells can be induced to differentiate into skeletal muscle cells, central rawhide sarcomere, and classic brown adipocytes [30]. White adipocytes are formed by the differentiation of the vascular and stromal layer by Myf5 − [31]. Therefore, the metabolic properties of BAT are more like those of the skeletal muscle cells and are primarily reflected in its structure and mitochondrial abundance in two ways. ...
... In mice experiments, IRISIN could increase the expression levels of UCP-1 and CIDEA in the white adipocytes. Similarly, the increased expression levels of IRISIN could also increase energy consumption, reduce body weight, and improve diet-induced insulin resistance [31]. A related study reported that, after 12 weeks of exercise, the levels of PGC-1α and FNDC5 (fibronectin type III domain containing 5) in prediabetes patients and healthy controls slightly increased [64]. ...
... Fat is an essential tissue in the living body, which can react and change according to the nutrient supply and changes in environmental temperature [28,31,203]. The beige adipocytes are produced by precursor cells in the process of adaptation to cold stimulation. ...
Mammalian adipose tissue can be divided into white and brown adipose tissue based on its colour, location, and cellular structure. Certain conditions, such as sympathetic nerve excitement, can induce the white adipose adipocytes into a new type of adipocytes, known as beige adipocytes. The process, leading to the conversion of white adipocytes into beige adipocytes, is called white fat browning. The dynamic balance between white and beige adipocytes is closely related to the body’s metabolic homeostasis. Studying the signal transduction pathways of the white fat browning might provide novel ideas for the treatment of obesity and alleviation of obesity-related glucose and lipid metabolism disorders. This article aimed to provide an overview of recent advances in understanding white fat browning and the role of BAT in lipid metabolism.
... Adipocytes of WAT and beige adipose tissue are predominantly derived from the Myf 5 negative progenitor cells, while adipocytes of BAT are predominantly from Myf 5 positive progenitor cells. Myf 5 or myogenic factor 5 is a gene for transcriptional factor expressed during embryonic myogenesis [68]. Brown and beige AT show anatomical decline with aging and protect from obesity and type 2 diabetes mellitus (T2DM). ...
Increase in body weight due to excess accumulation of fat can lead to obesity, a chronic, progressive, relapsing, multifactorial, neurobehavioral disease caused by adipose tissue dysfunction. Obesity often results in adverse biomechanical, metabolic, psychosocial, and economic consequences. In humans, effects of obesity are diverse and interrelated and can be classified on the basis of organ/organ system affected. Physical problems associated with weight gain are musculoskeletal problems, respiratory problems, lower limb venous diseases, skin-related problems, and stress incontinence in females. Metabolic conditions caused by obesity include gout, insulin resistance and metabolic syndrome, type 2 diabetes mellitus, certain cancers, CVD, fatty liver, gall bladder disease, etc. Obesity is known to affect the reproductive health. Hypogonadism and pseudo-gynecomastia are more common in males with obesity. Decreased fertility is reported in both the sexes. Polycystic ovarian syndrome (PCOS), anovulation, endometrial hyperplasia, and increased risk of complications in pregnancy have been reported in females. Persons with obesity have increased healthcare expense, pay more insurance premium, take more illness-related leaves, thus suffering economic loss due to their condition. Persons with obesity are often considered legitimate targets for teasing and bullying, which may cause social isolation, depression, eating disorders, etc. Obesity affects the morbidity and mortality. This chapter deals with the different consequences of obesity.
... During cold acclimatization, the adipose organ undergoes the phenomenon of browning (Fig. 2c). Such phenomenon occurs thanks to the differentiation of progenitors into mature brown adipocytes (Lee et al. 2012;Shan et al. 2013) and, based on our qualitative (Barbatelli et al. 2010;De Matteis et al. 2009;Cousin et al. 1992) and quantitative data (Vitali et al. 2012), to the direct transdifferentiation of white into brown adipocytes. Such phenomenon was also recently confirmed by lineage tracing experiments (Rosenwald et al. 2013). ...
Obesity is a complex, multifactorial, and relapsing disease whose prevalence has tripled during the last decades and whose incidence is expected to further increase. For these reasons, obesity is considered as a real pandemic, deeply burdening the global health-care systems. From a pathophysiological standpoint obesity is the result of a chronic-positive energy balance which in turn leads to an excessive accumulation of lipids, not only within the adipose organ, but also in different cytotypes, a phenomenon leading to lipotoxicity that deeply compromises several cellular and organs functions. Obesity is therefore associated with over 200 medical complications, including insulin resistance and type 2 diabetes mellitus (T2DM) and represents the fifth leading cause of death worldwide. In this review, we describe the main pathophysiological mechanisms linking obesity-induced adipose organ dysfunction to insulin resistance and T2DM.
... Embryonic origin is also different between beige and brown adipocytes. Brown adipocytes arise from the progenitors that express myogenic factor 5 (Myf5), whereas white and beige adipocytes are predominately generated from the non-Myf5-lineage progenitors (10). Beige adipocytes can be differentiated in multiple ways. ...
Beige adipocyte, the third and relatively new type of adipocyte, can emerge in white adipose tissue (WAT) under thermogenic stimulations that is termed as browning of WAT. Recent studies suggest that browning of WAT deserves more attention and therapies targeting browning of WAT can be helpful for reducing obesity. Beyond the major inducers of browning, namely cold and β3-adrenergic stimulation, beige adipocytes are affected by several factors, and excess adiposity per se may also influence the browning process. The objective of the present review is to provide an overview of recent clinical and preclinical studies on the hormonal and non-hormonal factors that affect the browning of WAT. This review further focuses on the role of obesity per se on browning process.
