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The cellular and functional complexity of thermogenic fat

Nature Reviews Molecular Cell Biology volume 22, pages 393–409 (2021)Cite this article

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Abstract

Brown and beige adipocytes are mitochondria-enriched cells capable of dissipating energy in the form of heat. These thermogenic fat cells were originally considered to function solely in heat generation through the action of the mitochondrial protein uncoupling protein 1 (UCP1). In recent years, significant advances have been made in our understanding of the ontogeny, bioenergetics and physiological functions of thermogenic fat. Distinct subtypes of thermogenic adipocytes have been identified with unique developmental origins, which have been increasingly dissected in cellular and molecular detail. Moreover, several UCP1-independent thermogenic mechanisms have been described, expanding the role of these cells in energy homeostasis. Recent studies have also delineated roles for these cells beyond the regulation of thermogenesis, including as dynamic secretory cells and as a metabolic sink. This Review presents our current understanding of thermogenic adipocytes with an emphasis on their development, biological functions and roles in systemic physiology.

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Fig. 1: Characteristics and anatomical distribution of thermogenic adipocytes.
Fig. 2: Beige fat biogenesis.
Fig. 3: Regulation and heterogeneity of thermogenic fat.
Fig. 4: Thermogenic mechanisms in adipocytes.
Fig. 5: The multifaceted roles of brown and beige fat.
Fig. 6: Harnessing thermogenic fat activity for precision medicine.

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Acknowledgements

The authors apologize for being unable to cite large numbers of important contributions to the field due to space limitations. This work was supported by the American Diabetes Association Pathway Program (1-17-ACE-17) to P.C., and by the National Institutes of Health (NIH) (DK097441, DK125281, DK126160, DK127575, DK125283) and the Edward Mallinckrodt, Jr. Foundation to S.K.

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Authors and Affiliations

  1. Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY, USA

    Paul Cohen

  2. Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Shingo Kajimura

  3. Department of Cell and Tissue Biology, UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA, USA

    Shingo Kajimura

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  1. Paul Cohen
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  2. Shingo Kajimura
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Both authors contributed equally to this work.

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Correspondence to Paul Cohen or Shingo Kajimura.

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Nature Reviews Molecular Cell Biology thanks M. Saito, F. Villarroya and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Cristae

Folds in the inner membrane of a mitochondrion where active electron transport takes place.

Catecholamines

Monoamine neurotransmitters that mediate cold-induced thermogenesis.

Thiazolidinediones

(Also known as glitazones). Synthetic ligands of PPARγ typically used in the treatment of type 2 diabetes. They also increase thermogenesis and have been shown to promote recruitment of beige thermogenic adipocytes.

Dermomyotome

Epithelial tissue present during development that combines a dermatome (giving rise to the epidermis) and a myotome (giving rise to skeletal muscle) before they separate in embryogenesis.

Retroperitoneal WAT

White adipose tissue (WAT) in the area between the posterior portion of the parietal peritoneum and the posterior abdominal wall muscles.

β3-Adrenergic signalling

Signalling potently stimulated by cold that is mediated by catecholamines that bind to β3-adrenergic receptors (β3-ARs), G protein-coupled receptors that activate adenylate cyclase to produce a second messenger cAMP.

Inguinal WAT

Subcutaneous adipose tissue located at the juncture of the lower portion of the anterior abdominal wall and legs. Inguinal white adipose tissue (WAT) contains high levels of beige adipocytes.

Insulin resistance

Insulin acts on the insulin receptor on the plasma membrane of target organs and triggers insulin signalling to stimulate anabolic reactions. Insulin action is impaired under insulin resistance conditions, which can eventually lead to type 2 diabetes.

Mitophagy

A selective mechanism to degrade defective mitochondria by autophagy.

Natriuretic peptides

Peptide hormones that induce sodium excretion by the kidney, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and dendroaspis natriuretic peptide (DNP).

Myokine

A secretory molecule released from skeletal muscle. Examples include IL-6 and irisin, both of which are known to activate thermogenic fat biogenesis.

Adiponectin

A fat-selective secretory protein hormone (adipokine) that is involved in regulating glucose and lipid homeostasis. In general, adiponectin levels are positively correlated with metabolic health.

Ancillary/niche cells

Supporting cells releasing paracrine factors.

Epididymal WAT

Visceral adipose tissue attached to the epididymis. Epididymal white adipose tissue (WAT) is known to have lower beiging propensity relative to inguinal WAT of mice.

γδ T cells

A subset of T cells that express a distinctive set (γ and δ-chains) of T cell receptor (TCR) on their surface, distinct from that of conventional T cells (αβ T cells).

Group 2 innate lymphoid cells

(ILC2s). A subset of innate lymphoid cells that produce type 2 cytokines, such as IL-5 and IL-13.

Methionine-enkephalin

(MetEnk). An endogenous opioid peptide that acts on δ-opioid receptor and μ-opioid receptor to a lesser extent.

Mast cells

Immune cells that release histamine and other substances during inflammatory and allergic reactions.

Invariant natural killer T cells

(iNKT cells). Specialized T cells that recognize lipid antigens.

α-Galactosylceramide

(α-GalCer). A synthetic glycolipid that stimulates invariant natural killer T cells.

Liraglutide

A glucagon-like peptide 1 receptor (GLP1R) agonist that acts as an incretin mimetic and increases insulin secretion.

Respiratory chain

(Also known as electron transport chain). Multiple protein complexes that transfer electrons from electron donors, such as NADH, to electron acceptors, thereby generating a proton (H+) gradient across the mitochondrial inner membrane.

Oxidative phosphorylation

A metabolic process in which cells use series of enzymes to oxidize glucose, fatty acids and other metabolites to produce ATP.

Acylcarnitine

A metabolite derived from carnitine and acyl-coenzyme A (acyl-CoA). Generation of acylcarnitine allows the transport of fatty acids into the mitochondrial matrix for oxidation.

Sulfenylation

A post-translational protein modification involving the addition of a sulfenyl group to cysteine residues.

Succinylation

A post-translational modification in which a succinyl group is added to proteins at lysine residues.

Sirtuin

A protein with NAD-dependent deacetylase activity that plays key roles in cellular homeostasis, including ageing, transcription, stress response, inflammation and apoptosis.

5′ AMP-activated protein kinase

(AMPK). A heterotrimeric enzyme complex that is activated in response to low cellular ATP, including low glucose and hypoxia, and stimulates glucose and fatty acid catabolism and autophagy.

Leptin

An adipocyte-derived hormone that regulates food intake and energy expenditure.

N-Acyl amino acids

Lipids that contain a fatty-acid tail covalently conjugated to an amino acid head group.

Triglyceride-rich lipoproteins

Lipoproteins that transport triglycerides and cholesterol; these include very low-density lipoprotein (VLDL) and chylomicrons.

Reverse cholesterol transport

A process in which cholesterol from peripheral organs is returned to the liver via the circulation.

Mevalonate pathway

A metabolic pathway for the synthesis of sterols and isoprenoids.

Bariatric surgery

A surgical procedure that promotes weight loss. These procedures include the Roux-en-Y gastric bypass, sleeve gastrectomy, adjustable gastric band and biliopancreatic diversion with duodenal switch.

Oxylipin

An oxygenated lipid derived from polyunsaturated fatty acid.

β-Hydroxybutyrate

(BHB). A major form of ketone bodies that is generated through fatty acid oxidation or leucine oxidation.

18F-fluorodeoxyglucose positron emission tomography combined with computed tomography

(FDG-PET/CT). An imaging-based technique that measures the uptake of a radioactive glucose analogue.

Chenodeoxycholic acid

A primary bile acid synthesized in the liver.

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Cohen, P., Kajimura, S. The cellular and functional complexity of thermogenic fat. Nat Rev Mol Cell Biol 22, 393–409 (2021). https://doi.org/10.1038/s41580-021-00350-0

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