Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis.

The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.

Unraveling the Developmental Roadmap toward Human Brown Adipose Tissue.

Increasing brown adipose tissue (BAT) mass and activation is a therapeutic strategy to treat obesity and complications. Obese and diabetic patients possess low amounts of BAT, so an efficient way to expand their mass is necessary. There is limited knowledge about how human BAT develops, differentiates, and is optimally activated. Accessing human BAT is challenging, given its low volume and anatomical dispersion. These constraints make detailed BAT-related developmental and functional mechanistic studies in humans virtually impossible. We have developed and characterized functionally and molecularly a new chemically defined protocol for the differentiation of human pluripotent stem cells (hPSCs) into brown adipocytes (BAs) that overcomes current limitations. This protocol recapitulates step by step the physiological developmental path of human BAT. The BAs obtained express BA and thermogenic markers, are insulin sensitive, and responsive to ß-adrenergic stimuli. This new protocol is scalable, enabling the study of human BAs at early stages of development.

Studying Brown Adipose Tissue in a Human in vitro Context.

New treatments for obesity and associated metabolic disease are increasingly warranted with the growth of the obesity pandemic. Brown adipose tissue (BAT) may represent a promising therapeutic target to treat obesity, as this tissue has been shown to regulate energy expenditure through non-shivering thermogenesis. Three different strategies could be employed for therapeutic targeting of human thermogenic adipocytes: increasing BAT mass through stimulation of BAT progenitors, increasing BAT function through regulatory pathways, and increasing WAT browning through promotion of beige adipocyte formation. However, these strategies require deeper understanding of human brown and beige adipocytes. While murine studies have greatly increased our understanding of BAT, it is becoming clear that human BAT does not exactly resemble that of the mouse, highlighting the need for human in vitro models of brown adipocytes. Several different human brown adipocyte models will be discussed here, along with the potential to improve brown adipocyte culture through recreation of the BAT microenvironment.

Publisher Correction: Enhanced ß-adrenergic signalling underlies an age-dependent beneficial metabolic effect of PI3K p110α inactivation in adipose tissue.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Gain of Metabolic Benefit with Ablation of miR-149-3p from Subcutaneous Adipose Tissue in Diet-Induced Obese Mice.

The global rise in obesity has become a public health crisis. During the onset of obesity, disrupted catecholamine signals have been described to contribute to excess fat accumulation, however, the molecular and metabolic change of subcutaneous adipose tissue (SAT) upon chronic high-fat feeding has rarely been investigated. Here, we show that chronic high-fat feeding caused a significant decrease in the expression of thermogenic genes and acquisition of partial deleterious features of visceral fat in SAT. Upregulated miR-149-3p was involved in this obesity-induced "visceralization" of SAT via inhibiting PRDM16, a master regulator that promoted SAT thermogenesis. Reduction of miR-149-3p significantly increased PRDM16 expression in SAT, with improved whole-body insulin sensitivity, decreased SAT inflammation, and liver steatosis in high-fat fed mice. These findings provided direct evidence of the anti-obese and anti-diabetic effect of PRDM16 in the obese background for the first time and identified that miR-149-3p could serve as a therapeutic target to protect against diet-induced obesity and metabolic dysfunctions.

Enhanced ß-adrenergic signalling underlies an age-dependent beneficial metabolic effect of PI3K p110α inactivation in adipose tissue.

The insulin/IGF-1 signalling pathway is a key regulator of metabolism and the rate of ageing. We previously documented that systemic inactivation of phosphoinositide 3-kinase (PI3K) p110α, the principal PI3K isoform that positively regulates insulin signalling, results in a beneficial metabolic effect in aged mice. Here we demonstrate that deletion of p110α specifically in the adipose tissue leads to less fat accumulation over a significant part of adult life and allows the maintenance of normal glucose tolerance despite insulin resistance. This effect of p110α inactivation is due to a potentiating effect on ß-adrenergic signalling, which leads to increased catecholamine-induced energy expenditure in the adipose tissue. Our findings provide a paradigm of how partial inactivation of an essential component of the insulin signalling pathway can have an overall beneficial metabolic effect and suggest that PI3K inhibition could potentiate the effect of ß-adrenergic agonists in the treatment of obesity and its associated comorbidities.

Brown and beige fat: From molecules to physiology and pathophysiology.

The adipose organ portrays adipocytes of diverse tones: white, brown and beige, each type with distinct functions. Adipocytes orchestrate their adaptation and expansion to provide storage to excess nutrients, the quick mobilisation of fuel to supply peripheral functional demands, insulation, and, in their thermogenic form, heat generation to maintain core body temperature. Thermogenic adipocytes could be targets for anti-obesity and anti-diabetic therapeutic approaches aiming to restore adipose tissue functionality and increase energy dissipation. However, for thermogenic adipose tissue to become therapeutically relevant, a better understanding of its development and origins, its progenitors and their characteristics and the composition of its niche, is essential. Also crucial is the identification of stimuli and molecules promoting its specific differentiation and activation. Here we highlight the structural/cellular differences between human and rodent brown adipose tissue and discuss how obesity and metabolic complication affects brown and beige cells as well as how they could be targeted to improve their activation and improve global metabolic homeostasis. Finally, we describe the limitations of current research models and the advantages of new emerging approaches.

Fed-EXosome: extracellular vesicles and cell-cell communication in metabolic regulation.

Extracellular vesicles (EVs) have emerged as a novel messaging system of the organism, mediating cell-cell and interorgan communication. Through their content of proteins and nucleic acids, as well as membrane proteins and lipid species, EVs can interact with and modulate the function of their target cells. The regulation of whole-body metabolism requires cross-talk between key metabolic tissues including adipose tissue (AT), the liver and skeletal muscle. Furthermore, the regulation of nutrient/energy allocation during pregnancy requires co-ordinated communication between the foetus and metabolic organs of the mother. A growing body of evidence is suggesting that EVs play a role in communication between and within key metabolic organs, both physiologically during metabolic homoeostasis but also contributing to pathophysiology during metabolic dysregulation observed in metabolic diseases such as obesity and diabetes. As obesity and its associated metabolic complications are reaching epidemic proportions, characterization of EV-mediated communication between key metabolic tissues may offer important insights into the regulation of metabolic functions during disease and offer global therapeutic opportunities. Here, we focus on the role of EVs in metabolic regulation and, in particular, EV-mediated cross-talk between cells of the AT.