bims-mimeim 2021-05-30 papers

Issue of 2021‒05‒30
four papers selected by
Matthew C. Sinton, University of Glasgow

Cell. 2021 May 22. pii: S0092-8674(21)00572-9. [Epub ahead of print]

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis.

Olivia Sveidahl Johansen, Tao Ma, Jakob Bondo Hansen, Lasse Kruse Markussen, Renate Schreiber, Laia Reverte-Salisa, Hua Dong, Dan Ploug Christensen, Wenfei Sun, Thorsten Gnad, Iuliia Karavaeva, Thomas Svava Nielsen, Sander Kooijman, Cheryl Cero, Oksana Dmytriyeva, Yachen Shen, Maria Razzoli, Shannon L O'Brien, Eline N Kuipers, Carsten Haagen Nielsen, William Orchard, Nienke Willemsen, Naja Zenius Jespersen, Morten Lundh, Elahu Gosney Sustarsic, Cecilie Mørch Hallgren, Mikkel Frost, Seth McGonigle, Marie Sophie Isidor, Christa Broholm, Oluf Pedersen, Jacob Bo Hansen, Niels Grarup, Torben Hansen, Andreas Kjær, James G Granneman, M Madan Babu, Davide Calebiro, Søren Nielsen, Mikael Rydén, Raymond Soccio, Patrick C N Rensen, Jonas Thue Treebak, Thue Walter Schwartz, Brice Emanuelli, Alessandro Bartolomucci, Alexander Pfeifer, Rudolf Zechner, Camilla Scheele, Susanne Mandrup, Zachary Gerhart-Hines.

Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.

Keywords: G protein-coupled receptor; GPCR; GPR3; adrenergic receptor; brown adipose tissue; constitutively active; energy expenditure; lipolysis; thermogenesis; transcription

DOI: https://doi.org/10.1016/j.cell.2021.04.037

FEBS J. 2021 May 24.

Energy metabolism in brown adipose tissue.

Zhichao Wang, Qiong A Wang, Yong Liu, Lei Jiang.

Brown adipose tissue (BAT) is well known to burn calories through uncoupled respiration, producing heat to maintain body temperature. This 'calorie wasting' feature makes BAT a special tissue, which can function as an 'energy sink' in mammals. While a combination of high energy intake and low energy expenditure is the leading cause of overweight and obesity in modern society, activating a safe 'energy sink' has been proposed as a promising obesity treatment strategy. Metabolically, lipids and glucose have been viewed as the major energy substrates in BAT, while succinate, lactate, branched-chain amino acids, and other metabolites can also serve as energy substrates for thermogenesis. Since the cataplerotic and anaplerotic reactions of these metabolites interconnect with each other, BAT relies on its dynamic, flexible, and complex metabolism to support its special function. In this review, we summarize how BAT orchestrates the metabolic utilization of various nutrients to support thermogenesis and contributes to whole-body metabolic homeostasis.

Keywords: brown adipose tissue; glucose metabolism; metabolic flux; obesity; thermogenesis

DOI: https://doi.org/10.1111/febs.16015

Life Sci. 2021 May 24. pii: S0024-3205(21)00634-2. [Epub ahead of print] 119648

Cytochrome P450 2E1 (CYP2E1) positively regulates lipid catabolism and induces browning in 3T3-L1 white adipocytes.

Trang Thi Huyen Dang, Jong Won Yun.

AIMS: Browning induction (beiging) of white adipocytes is an emerging prospective strategy to defeat obesity and its related metabolic disorders. Cytochrome P450 2E1 (CYP2E1), a membrane protein which belongs to the cytochrome P450 superfamily, reportedly functions in the xenobiotic metabolism in the body, especially ethanol metabolism. Although previous studies have reported the effect of CYP2E1 on obesity in animal models, the data remains controversial. In the current study, we investigate for the first time, the role of CYP2E1 in lipid metabolism in 3T3-L1 white adipocytes, with a focus on fat browning.METHODS: 3T3-L1 white adipocytes and Cyp2e1 siRNA were apply to investigate the role of CYP2E1 in white adipocytes. After that, cells were seperately exposed to β3-AR agonist, β3-AR antagonist and p38 inhibitor to identify the pathway which CYP2E1 was involved in to regulate browning event in white adipocytes.
KEY FINDINGS: We found that CYP2E1 deficiency results in reduced adipogenesis and lipogenesis as well as brown adipocyte-like phenotype induction. A mechanistic study to identify the molecular signals for CYP2E1 regulation in the browning of white adipocytes revealed that CYP2E1 inhibition deters the β3-adrenergic receptor activation and its downstream targets.
SIGNIFICANCE: Our data unveilved a previously unknown mechanism in the regulation of browning by CYP2E1 in 3T3-L1 white adipocytes, suggesting that CYP2E1 is a promising molecular target for the treatment of obesity and its related diseases.

Keywords: 3T3-L1 cells; Cytochrome P450 2E1; Fat browning; Obesity; Thermogenesis

DOI: https://doi.org/10.1016/j.lfs.2021.119648

Nat Metab. 2021 May;3(5): 714-727

Single-cell metabolic imaging reveals a SLC2A3-dependent glycolytic burst in motile endothelial cells.

David Wu, Devin L Harrison, Teodora Szasz, Chih-Fan Yeh, Tzu-Pin Shentu, Angelo Meliton, Ru-Ting Huang, Zhengjie Zhou, Gökhan M Mutlu, Jun Huang, Yun Fang.

Single-cell motility is spatially heterogeneous and driven by metabolic energy. Directly linking cell motility to cell metabolism is technically challenging but biologically important. Here, we use single-cell metabolic imaging to measure glycolysis in individual endothelial cells with genetically encoded biosensors capable of deciphering metabolic heterogeneity at subcellular resolution. We show that cellular glycolysis fuels endothelial activation, migration and contraction and that sites of high lactate production colocalize with active cytoskeletal remodelling within an endothelial cell. Mechanistically, RhoA induces endothelial glycolysis for the phosphorylation of cofilin and myosin light chain in order to reorganize the cytoskeleton and thus control cell motility; RhoA activation triggers a glycolytic burst through the translocation of the glucose transporter SLC2A3/GLUT3 to fuel the cellular contractile machinery, as demonstrated across multiple endothelial cell types. Our data indicate that Rho-GTPase signalling coordinates energy metabolism with cytoskeleton remodelling to regulate endothelial cell motility.

DOI: https://doi.org/10.1038/s42255-021-00390-y