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Control of brown and beige fat development

Key Points

  • Brown and beige adipocytes are thermogenic fat cells that are highly specialized in dissipating chemical energy in the form of heat. There is great hope that these cells can be targeted therapeutically to combat obesity, insulin resistance and type 2 diabetes.

  • Brown adipocytes develop in distinctive developmental depots of brown adipose tissue (BAT) and have a relatively stable thermogenic phenotype. These cells are poised for heat production in response to various stimuli, including catecholamines that are secreted by sympathetic nerves in BAT on cold exposure.

  • Beige adipocytes are uncoupling protein 1 (UCP1)-expressing and thermogenically competent adipocytes that form in white adipose tissue (WAT) depots in response to various stimuli, including cold exposure or β3-adrenergic agonists. The beige phenotype of WAT is flexible, and the maintenance of beige cells requires ongoing stimulation.

  • Beige adipocytes can arise from adipogenic precursor cells in WAT through de novo differentiation or through the direct conversion of mature unilocular white-like adipocytes.

  • Brown and beige fat cells express certain transcription factors, such as early B-cell factor 2 (EBF2), PR domain zinc finger protein 16 (PRDM16), interferon regulatory factor 4 (IRF4) and zinc finger protein 516 (ZFP516), that cooperate with the general adipogenic factors peroxisome proliferator-activated receptor-γ (PPARγ) and the CCAAT/enhancer-binding proteins (C/EBPs) to drive brown adipocyte differentiation and thermogenic gene programming. ZFP423 acts in white adipocytes to suppress EBF2 and maintain white fat fate.

  • Type 2 cytokine signalling and alternative macrophage activation play a crucial part in regulating both brown fat thermogenesis and beige fat biogenesis. Alternatively activated macrophages secrete catecholamines in WAT to promote browning.

Abstract

Brown and beige adipocytes expend chemical energy to produce heat and are therefore important in regulating body temperature and body weight. Brown adipocytes develop in discrete and relatively homogenous depots of brown adipose tissue, whereas beige adipocytes are induced to develop in white adipose tissue in response to certain stimuli — notably, exposure to cold. Fate-mapping analyses have identified progenitor populations that give rise to brown and beige fat cells, and have revealed unanticipated cell-lineage relationships between vascular smooth muscle cells and beige adipocytes, and between skeletal muscle cells and brown fat. In addition, non-adipocyte cells in adipose tissue, including neurons, blood vessel-associated cells and immune cells, have crucial roles in regulating the differentiation and function of brown and beige fat.

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Figure 1: Brown, white and beige adipocytes.
Figure 2: Development of brown adipocytes.
Figure 3: Development of beige adipocytes.
Figure 4: Crosstalk between brown and/or beige adipocytes and other adipose-resident cells.

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Acknowledgements

This work was supported by an American Heart Association postdoctoral fellowship to W.W. and US National Institute of Diabetes and Digestive and Kidney Diseases grant 5R01DK10300802 to P.S.

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Correspondence to Patrick Seale.

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Summary of lineage tracing studies. (PDF 2865 kb)

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Glossary

Sympathetic nervous system

(SNS). Regulates bodily function (unconsciously) by connecting the brain to internal organs through nerves in the spinal column. Presynaptic neurons in the spinal cord secrete acetylcholine to activate postsynaptic neurons that innervate target organs and tissues. The postsynaptic neurons secrete noradrenaline, which activates β-adrenergic receptors on various cell types, including adipocytes.

Noradrenaline

A neurotransmitter in the catecholamine family that is secreted by sympathetic neurons to stimulate various responses, including adaptive thermogenesis in brown and beige fat.

Adrenergic receptors

A class of G protein-coupled cell surface receptors that are activated by catecholamines.

Adaptive thermogenesis

A facultative process by which animals produce heat only in response to stimuli, such as cold exposure or high-fat diet. Muscle shivering and uncoupled respiration in brown and beige fat are major mechanisms.

Thiazolidinediones

A class of synthetic high-affinity agonists for the nuclear hormone receptor peroxisome proliferator-activated receptor-γ (PPARγ). Thiazolidinediones improve insulin action in mice and humans through activation of PPARγ in adipocytes and other cell types.

Homeobox gene

A family of genes that encode proteins that are characterized by a DNA sequence called the homeobox. Members of this gene family have crucial roles in patterning and morphogenesis.

Dermomyotome

The mesodermal domain of the somite that is fated to differentiate into the skeletal muscle (myotome) and dermis (dermatome).

Helix–loop–helix transcription factor

A transcription factor family characterized by a structural motif. These factors are known to have important roles in various developmental processes.

Mural cells

Cells that are closely associated with the vasculature, such as vascular smooth muscle cells or pericytes.

Catecholamine

A class of naturally occurring chemicals, including noradrenaline and adrenaline, that act as neurotransmitters.

M1-like macrophages

Macrophage populations that have a pro-inflammatory profile and are characterized by secretion of interferon-γ, tumour necrosis factor and interleukin-1.

M2-like macrophages

Alternatively activated macrophage populations that are characterized by secretion of arginase and interleukin-10, and that have important roles in tissue repair and homeostasis.

Eosinophils

Specialized white blood cells that are characterized by granules that contain histamine and other chemical mediators. They play an important part in anti-parasite immunity.

Lipolysis

Hydrolysis of lipids into their component free fatty acids and glycerol.

Met-encephalin

A type of encephalin, which is a five-amino-acid peptide that is classically known to regulate nociception by binding to opioid receptors. Met-encephalin contains methionine, whereas Leu-encephalin contains leucine.

Adipokine

Cytokine or other protein secreted by adipocytes.

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Wang, W., Seale, P. Control of brown and beige fat development. Nat Rev Mol Cell Biol 17, 691–702 (2016). https://doi.org/10.1038/nrm.2016.96

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