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Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics

Abstract

In mammals, the white adipocyte is a cell type that is specialized for storage of energy (in the form of triacylglycerols) and for energy mobilization (as fatty acids). White adipocyte metabolism confers an essential role to adipose tissue in whole-body homeostasis. Dysfunction in white adipocyte metabolism is a cardinal event in the development of insulin resistance and associated disorders. This Review focuses on our current understanding of lipid and glucose metabolic pathways in the white adipocyte. We survey recent advances in humans on the importance of adipocyte hypertrophy and on the in vivo turnover of adipocytes and stored lipids. At the molecular level, the identification of novel regulators and of the interplay between metabolic pathways explains the fine-tuning between the anabolic and catabolic fates of fatty acids and glucose in different physiological states. We also examine the metabolic alterations involved in the genesis of obesity-associated metabolic disorders, lipodystrophic states, cancers and cancer-associated cachexia. New challenges include defining the heterogeneity of white adipocytes in different anatomical locations throughout the lifespan and investigating the importance of rhythmic processes. Targeting white fat metabolism offers opportunities for improved patient stratification and a wide, yet unexploited, range of therapeutic opportunities.

Key points

  • White adipocyte size and turnover are determinants of systemic insulin sensitivity and cardiometabolic phenotype in humans.

  • White adipocytes are specialized in fat storage and mobilization; the underlying lipid metabolic pathways are tightly connected with those governing the intracellular fate of glucose.

  • In some fat depots, there is a bidirectional switch between white and beige adipocytes, which display an oxidative phenotype with energy dissipation through uncoupling protein 1 (UCP1)-dependent and UCP1-independent pathways.

  • White adipocyte metabolic pathways control the secretion of proteins and lipids with local and systemic effects on inflammation and insulin sensitivity.

  • Adipocyte metabolism offers promising targets for the treatment of cardiometabolic diseases and cancer-associated disorders.

  • Future research will include the in-depth characterization of adipocyte diversity associated with anatomical location, age, sex and physiological rhythms.

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Fig. 1: Timeline of important advances and promising discoveries in white adipose tissue research.
Fig. 2: Turnover of human white adipose tissue.
Fig. 3: Fat storage and glucose metabolism in white adipocytes.
Fig. 4: Fat mobilization in white adipocytes.
Fig. 5: Energy dissipation in adipocytes.
Fig. 6: Crosstalk between metabolic pathways in the white adipocyte.
Fig. 7: Systemic impact of adipocyte metabolism and therapeutic perspectives.

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Acknowledgements

The rapid growth of research in adipocyte metabolism made it impossible to cite a large number of excellent studies relevant to the topic of this review. D.L. is supported by Inserm, Paul Sabatier University, European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (SPHERES, ERC Synergy Grant agreement No. 856404), Fondation pour la Recherche Médicale (DEQ20170336720), Agence Nationale de la Recherche (ANR-17-CE14-0015Hepadialogue), Région Occitanie (DIALOGUE projects), FORCE/F-CRIN and AstraZeneca France. D.L. is a member of Institut Universitaire de France.

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D.L. conceived the initial version of the article. All authors wrote the article. P.M. and P.A. prepared the figures. D.L. integrated contributions and produced the submitted version with input from P.M., J.B. and P.A. All authors approved the final version of the article.

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Correspondence to Dominique Langin.

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J.B. is an employee of AstraZeneca. The other authors declare no competing interests.

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Nature Reviews Endocrinology thanks J.-H. Chen, who co-reviewed with S. O’Rahilly; M. Czech; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Adipose tissue hypertrophy

Adipose tissue expansion through an increase in adipocyte size.

Adipose tissue hyperplasia

Adipose tissue expansion through the generation of new adipocytes.

M1-like macrophage

Subtype of macrophages characterized by the secretion of pro-inflammatory cytokines and chemokines, such as IL-6 and tumour necrosis factor.

Lipophagy

Triacylglycerol hydrolysis by lysosomal acid lipases after engulfment of a lipid droplet by an autophagosome, which fuses with lysosomes.

Beige adipocytes

Also known as brown-in-white (brite) adipocytes. A subtype of thermogenic adipocytes located in white fat depots and uniquely equipped to dissipate energy as heat.

Pyroptotic cell death

Cell death triggered by pro-inflammatory signals and subsequent activation of the NLRP3 inflammasome.

Lipocalins

Small extracellular proteins that are responsible for the transport of hydrophobic molecules, such as lipids, steroids and retinoids, in the circulation.

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Morigny, P., Boucher, J., Arner, P. et al. Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics. Nat Rev Endocrinol 17, 276–295 (2021). https://doi.org/10.1038/s41574-021-00471-8

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