Thermogenic Activity of UCP1 in Human White Fat-Derived Beige Adipocytes

Bartesaghi, Stefano; Hallén, Stefan; Huang, Li; Svensson, Per‐Arne; Momo, Remi A.; Wallin, Simonetta; Carlsson, Eva; Forslöw, Anna; Seale, Patrick; Peng, Xiaorong

doi:10.1210/me.2014-1295

Cited by 84 publications

(75 citation statements)

References 32 publications

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“…In conjunction with other studies (40,48,49) that includes work performed in primary adipocytes (50), our data strongly suggest Ubc9 inhibits PPAR␥ activity, resulting in repression of thermogenic target genes and oxidative metabolism, a finding that is unlikely conserved in 3T3-L1 cells (26). Although it is still unclear whether acquisition of brown fat features in human WAT is sufficient to affect energy expenditure, recent data suggests thermogenesis in human adipose-derived stromal cells is UCP1-dependent (51). Therefore, we propose disruption of Ubc9 expression promotes the thermogenic specificity of PPAR␥ transcriptional programs in human white adipocytes and thus may enhance the insulin-sensitizing effects of PPAR␥-activating drugs.…”

Section: Discussionsupporting

confidence: 83%

Ubc9 Impairs Activation of the Brown Fat Energy Metabolism Program in Human White Adipocytes

Hartig

Bader

Abadie

et al. 2015

Molecular Endocrinology

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Insulin resistance and type 2 diabetes mellitus (T2DM) result from an inability to efficiently store and catabolize surplus energy in adipose tissue. Subcutaneous adipocytes protect against insulin resistance and T2DM by coupling differentiation with the induction of brown fat gene programs for efficient energy metabolism. Mechanisms that disrupt these programs in adipocytes are currently poorly defined, but represent therapeutic targets for the treatment of T2DM. To gain insight into these mechanisms, we performed a high-throughput microscopy screen that identified ubiquitin carrier protein 9 (Ubc9) as a negative regulator of energy storage in human sc adipocytes. Ubc9 depletion enhanced energy storage and induced the brown fat gene program in human sc adipocytes. Induction of adipocyte differentiation resulted in decreased Ubc9 expression commensurate with increased brown fat gene expression. Thiazolidinedione treatment reduced the interaction between Ubc9 and peroxisome proliferator-activated receptor (PPAR)γ, suggesting a mechanism by which Ubc9 represses PPARγ activity. In support of this hypothesis, Ubc9 overexpression remodeled energy metabolism in human sc adipocytes by selectively inhibiting brown adipocyte-specific function. Further, Ubc9 overexpression decreased uncoupling protein 1 expression by disrupting PPARγ binding at a critical uncoupling protein 1 enhancer region. Last, Ubc9 is significantly elevated in sc adipose tissue isolated from mouse models of insulin resistance as well as diabetic and insulin-resistant humans. Taken together, our findings demonstrate a critical role for Ubc9 in the regulation of sc adipocyte energy homeostasis.

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Section: Discussionsupporting

confidence: 83%

Ubc9 Impairs Activation of the Brown Fat Energy Metabolism Program in Human White Adipocytes

Hartig

Bader

Abadie

et al. 2015

Molecular Endocrinology

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“…It has been reported that in addition to the supraclavicular area, thermogenic adipocytes also exist in human subcutaneous fat depots [8, 10]. We observed a clear activation of the thermogenic response and PKA signaling in differentiated hASCs isolated from subcutaneous fat depots (Fig.…”

Section: Resultssupporting

confidence: 63%

Cinnamaldehyde induces fat cell-autonomous thermogenesis and metabolic reprogramming

et al. 2017

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Objective Cinnamaldehyde (CA) is a food compound that has previously been observed to be protective against obesity and hyperglycemia in mouse models. In this study, we aimed to elucidate the mechanisms behind this protective effect by assessing the cell-autonomous response of primary adipocytes to CA treatment. Methods Primary murine adipocytes were treated with CA and thermogenic and metabolic responses were assessed after both acute and chronic treatments. Human adipose stem cells were differentiated and treated with CA to assess whether the CA-mediated signaling is conserved in humans. Results CA significantly activated PKA signaling, increased expression levels of thermogenic genes and induced phosphorylation of HSL and PLIN1 in murine primary adipocytes. Inhibition of PKA or p38 MAPK enzymatic activity markedly inhibited the CA-induced thermogenic response. In addition, chronic CA treatment regulates metabolic reprogramming, which was partially diminished in FGF21KO adipocytes. Importantly, both acute and chronic effects of CA were observed in human adipose stem cells isolated from multiple donors of different ethnicities and ages and with a variety of body mass indexes (BMI). Conclusions CA activates thermogenic and metabolic responses in mouse and human primary subcutaneous adipocytes in a cell-autonomous manner, giving a mechanistic explanation for the anti-obesity effects of CA observed previously and further supporting its potential metabolic benefits on humans. Given the wide usage of cinnamon in the food industry, the notion that this popular food additive, instead of a drug, may activate thermogenesis, could ultimately lead to therapeutic strategies against obesity that are much better adhered to by participants.

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“…However, recent studies reported that stem cells from human WAT treated with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone 79 or bone morphogenetic protein 7 80 easily differentiate toward beige adipocytes and markedly enhance oxygen consumption. In addition, bone morphogenetic protein 7-driven browning of adipocytes results in higher glucose and FA uptake than white adipocytes.…”

Section: Because [mentioning

confidence: 99%

Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis

Hoeke

Kooijman

Boon

et al. 2016

Circulation Research

146

138

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Atherosclerosis, for which hyperlipidemia is a major risk factor, is the leading cause of morbidity and mortality in Western society, and new therapeutic strategies are highly warranted. Brown adipose tissue (BAT) is metabolically active in human adults. Although positron emission tomography-computed tomography using a glucose tracer is the golden standard to visualize and quantify the volume and activity of BAT, it has become clear that activated BAT combusts fatty acids rather than glucose. Here, we review the role of brown and beige adipocytes in lipoprotein metabolism and atherosclerosis, with evidence derived from both animal and human studies. On the basis of mainly data from animal models, we propose a model in which activated brown adipocytes use their intracellular triglyceride stores to generate fatty acids for combustion. BAT rapidly replenishes these stores by internalizing primarily lipoprotein triglyceride-derived fatty acids, generated by lipoprotein lipasemediated hydrolysis of triglycerides, rather than by holoparticle uptake. As a consequence, BAT activation leads to the generation of lipoprotein remnants that are subsequently cleared via the liver provided that an intact apoElow-density lipoprotein receptor pathway is present. Through these mechanisms, BAT activation reduces plasma triglyceride and cholesterol levels and attenuates diet-induced atherosclerosis development. Initial studies suggest that BAT activation in humans may also reduce triglyceride and cholesterol levels, but potential antiatherogenic effects should be assessed in future studies. (Circ Res. 2016;118:173-182.

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Thermogenic Activity of UCP1 in Human White Fat-Derived Beige Adipocytes

Cited by 84 publications

References 32 publications

Ubc9 Impairs Activation of the Brown Fat Energy Metabolism Program in Human White Adipocytes

Ubc9 Impairs Activation of the Brown Fat Energy Metabolism Program in Human White Adipocytes

Cinnamaldehyde induces fat cell-autonomous thermogenesis and metabolic reprogramming

Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis

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