Proteomics-Based Comparative Mapping of the Secretomes of Human Brown and White Adipocytes Reveals EPDR1 as a Novel Batokine

Deshmukh, Atul S.; Peijs, Lone; Beaudry, Jacqueline L.; Jespersen, Naja Zenius; Nielsen, Carsten H.; Ma, Tao; Brunner, Andreas David; Larsen, Therese Juhlin; Bayarri‐Olmos, Rafael; Prabhakar, Bhargav S.; Helgstrand, Charlotte; Severinsen, Mai Charlotte Krogh; Holst, Birgitte; Kjær, Andreas; Tang-Christensen, Mads; Sanfridson, Annika; Garred, Peter; Privé, G.G.; Pedersen, Bente Klarlund; Gerhart-Hines, Zachary; Nielsen, Søren; Drucker, Daniel J.; Mann, Matthias; Schéele, Camilla

doi:10.1016/j.cmet.2019.10.001

Cited by 118 publications

(111 citation statements)

References 56 publications

(72 reference statements)

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“…5e). To investigate the involvement of secreted factors other than FGF21, we looked at the gene expression of commonly known batokines 35,36 . Some of these appear to be regulated by the Time (min)…”

Section: Transcriptional Profiling Reveals Fgf21-controlled Browningmentioning

confidence: 99%

Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice

et al. 2020

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Uncoupling protein 1 (UCP1) executes thermogenesis in brown adipose tissue, which is a major focus of human obesity research. Although the UCP1-knockout (UCP1 KO) mouse represents the most frequently applied animal model to judge the anti-obesity effects of UCP1, the assessment is confounded by unknown anti-obesity factors causing paradoxical obesity resistance below thermoneutral temperatures. Here we identify the enigmatic factor as endogenous FGF21, which is primarily mediating obesity resistance. The generation of UCP1/FGF21 double-knockout mice (dKO) fully reverses obesity resistance. Within mild differences in energy metabolism, urine metabolomics uncover increased secretion of acylcarnitines in UCP1 KOs, suggesting metabolic reprogramming. Strikingly, transcriptomics of metabolically important organs reveal enhanced lipid and oxidative metabolism in specifically white adipose tissue that is fully reversed in dKO mice. Collectively, this study characterizes the effects of endogenous FGF21 that acts as master regulator to protect from diet-induced obesity in the absence of UCP1.

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Section: Transcriptional Profiling Reveals Fgf21-controlled Browningmentioning

confidence: 99%

Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice

et al. 2020

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“…This was in contrast to what has previously been reported in studies using glucose tracer uptake during cooling as a marker of BAT activity 17,29,30 . A possible explanation for this discrepancy, is that the biopsies in our cohort were obtained at room temperature where variations in UCP1 might not reflect thermogenic capacity to the same extent as when subjects are subjected to cold, as UCP1 is highly induced in brown adipocytes upon norepinephrine stimulation 31,32 . However, most subjects having UCP1 mRNA levels within the highest range were non-obese individuals.…”

Section: Resultsmentioning

confidence: 93%

Thermogenic genes are blunted whereas brown adipose tissue identity is preserved in human obesity

et al. 2020

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Obesity associates with a reduction in cold-induced glucose tracer uptake in brown adipose tissue in humans, suggesting loss of thermogenic capacity. We therefore hypothesized that a whitening of BAT occurs in obesity and assessed the molecular characteristics of deep neck BAT in a cohort of 24 normal weight, 24 overweight and 22 obese individuals in comparison with subcutaneous abdominal white adipose tissue (WAT). We found that the major marker of BAT thermogenesis, UCP1, was associated with central but not general obesity. We performed transcriptomic analysis of BAT in a cohort of 27 individuals classified as normal weight, over-weight or obese, and additionally four subjects with type 2 diabetes (T2DM), dispersed among the 3 BMI groups. We identified 3204 differentially expressed genes between BAT and WAT in samples from normal weight individuals, including genes involved in thermogenesis, but also revealing differences in developmental and immune system related genes. In BAT from individuals with overweight or obesity, 202 genes were downregulated and 66 of these were involved in cellular respiratory pathways, likely reflecting previously observed reduction in thermogenic function with obesity. Importantly, most BAT selective genes were not affected, and isolated adipose progenitors differentiated into thermogenic adipocytes with equal frequency regardless of BMI group. In conclusion, our data suggest a retained BAT identity, with a selective reduction of thermogenic genes, in human obesity.

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“…Brown adipocytes precursors can transdifferentiate into white or beige, as wells as precursors of white adipocytes can differentiate into brown and beige ( 14 ). The brown adipose tissue (BAT) is related to a higher thermogenic activity, supporting non-shivering thermogenesis, and recently identified and characterized by proteomics-based analysis, secreted factors from BAT, known as batokines, targeting immune cells, regulating glucose homeostasis and insulin sensitivity, angiogenesis, and neurite outgrowth ( 15 , 16 ). Recent studies have shown the role of miRNA in adipocyte development, metabolic functions, proliferation, and differentiation ( 17 ).…”

Section: Adipose Tissue and Macrophagesmentioning

confidence: 99%

The Impact of Adipose Tissue–Derived miRNAs in Metabolic Syndrome, Obesity, and Cancer

2020

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Obesity is a multifactorial and complex condition that is characterized by abnormal and excessive white adipose tissue accumulation, which can lead to the development of metabolic diseases, such as type 2 diabetes mellitus, nonalcoholic fatty liver disease, cardiovascular diseases, and several types of cancer. Obesity is characterized by excessive adipose tissue accumulation and associated with alterations in immunity, displaying a chronic low-grade inflammation profile. Adipose tissue is a dynamic and complex endocrine organ composed not only by adipocytes, but several immunological cells, which can secrete hormones, cytokines and many other factors capable of regulating metabolic homeostasis and several critical biological pathways. Remarkably, adipose tissue is a major source of circulating microRNAs (miRNAs), recently described as a novel form of adipokines. Several adipose tissue–derived miRNAs are deeply associated with adipocytes differentiation and have been identified with an essential role in obesity-associated inflammation, insulin resistance, and tumor microenvironment. During obesity, adipose tissue can completely change the profile of the secreted miRNAs, influencing circulating miRNAs and impacting the development of different pathological conditions, such as obesity, metabolic syndrome, and cancer. In this review, we discuss how miRNAs can act as epigenetic regulators affecting adipogenesis, adipocyte differentiation, lipid metabolism, browning of the white adipose tissue, glucose homeostasis, and insulin resistance, impacting deeply obesity and metabolic diseases. Moreover, we characterize how miRNAs can often act as oncogenic and tumor suppressor molecules, significantly modulating cancer establishment and progression. Furthermore, we highlight in this manuscript how adipose tissue–derived miRNAs can function as important new therapeutic targets.

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Proteomics-Based Comparative Mapping of the Secretomes of Human Brown and White Adipocytes Reveals EPDR1 as a Novel Batokine

Abstract: Highlights d Identification of the first human brown fat secretome d Comparative analysis of the secretomes of human brown and white adipocytes d 101 proteins were exclusively identified in the secretome of brown adipocytes d EPDR1 is a novel batokine important for brown fat commitment

Cited by 118 publications

References 56 publications

Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice

Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice

Thermogenic genes are blunted whereas brown adipose tissue identity is preserved in human obesity

The Impact of Adipose Tissue–Derived miRNAs in Metabolic Syndrome, Obesity, and Cancer

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