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Adipogenesis and metabolic health

Abstract

Obesity is characterized by increased adipose tissue mass and has been associated with a strong predisposition towards metabolic diseases and cancer. Thus, it constitutes a public health issue of major proportion. The expansion of adipose depots can be driven either by the increase in adipocyte size (hypertrophy) or by the formation of new adipocytes from precursor differentiation in the process of adipogenesis (hyperplasia). Notably, adipocyte expansion through adipogenesis can offset the negative metabolic effects of obesity, and the mechanisms and regulators of this adaptive process are now emerging. Over the past several years, we have learned a considerable amount about how adipocyte fate is determined and how adipogenesis is regulated by signalling and systemic factors. We have also gained appreciation that the adipogenic niche can influence tissue adipogenic capability. Approaches aimed at increasing adipogenesis over adipocyte hypertrophy can now be explored as a means to treat metabolic diseases.

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Fig. 1: Mechanisms of adipose tissue expansion.
Fig. 2: Overview of molecular mechanisms of adipogenesis.
Fig. 3: Sites of adult adipogenesis.
Fig. 4: Regulators of adipogenesis.

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Acknowledgements

The authors apologize to their colleagues for not being able to include all their important work related to adipogenesis and metabolic health. The authors also thank members of the Touchstone Diabetes Center for their helpful critical reading of this manuscript. P.E.S. is supported by US National Institutes of Health (NIH) grants R01-DK55758, P01-DK088761, R01-DK099110 and P01-AG051459 and by an unrestricted grant from the Novo Nordisk Research Foundation. A.L.G. is supported by the NIH, National Institute of General Medical Sciences Training Grant T32-GM008203.

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Nature Reviews Molecular Cell Biology thanks K. Spalding and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Correspondence to Philipp E. Scherer.

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Glossary

Insulin resistance

A pathological condition in which the systemic and cellular response to insulin action is impaired. At the cellular level, insulin resistance can be defined as reduced signal transduction along the PI3K–AKT–mTOR pathway per unit of insulin, resulting in decreased glucose uptake per unit of insulin in adipocytes and skeletal muscle or decreased suppression of hepatic gluconeogenesis. Systemically, compared with healthy individuals, individuals with insulin resistance have elevated plasma insulin levels, elevated plasma glucose levels and impaired glucose clearance in response to the same bolus of insulin.

Lipotoxicity

A cellular dysfunction arising from accumulation of lipid intermediates in cells other than adipocytes. In liver, accumulation of lipids contributes to the pathogenesis of non-alcoholic fatty liver disease and to insulin resistance. Lipid accumulation in skeletal muscle can contribute to insulin resistance, whereas in cardiac muscle, it can cause apoptotic cell death. Pancreatic lipid accumulation can lead to dysregulation of β-cell insulin secretion, and ultimately to apoptotic cell death.

Adipokines

Signalling molecules (proteins or lipids) secreted from adipose tissue.

Euthermic

A term referring to an animal that maintains a constant body temperature.

Interscapular depot

The brown adipose tissue depot found between the scapulae in rodents and infant humans.

Supraclavicular depot

The thermogenic adipose tissue depot found above the clavicles in adult humans and mice, which in humans contains the highest proportion, by volume, of total brown adipose tissue.

Sympathetic output

The sympathetic nervous system is a system of peripheral nerves that signal primarily with the neurotransmitter noradrenaline through activation of adrenergic receptors. Sympathetic output refers to central signals that increase the activity of these nerves.

Gluconeogenesis

The generation of glucose from non-carbohydrate carbon sources (glycerol, odd-chain fatty acids, lactate or certain amino acids). In mammals, the liver, kidney, intestine and skeletal muscle are the only organs capable of gluconeogenesis.

Ceramides

A class of sphingolipids extensively reported to contribute to insulin resistance. The anti-diabetic adipokine adiponectin exhibits effects partially through receptor-associated ceramidase activity.

Mesenchymal precursor

A stromal, fibroblast-like cell found throughout the body that is capable of differentiating to form an adipocyte, chondrocyte or osteoblast.

Nuclear hormone receptor

A class of nuclear receptors capable of directly binding to both DNA and a steroid or other endocrine hormone. Nuclear hormone receptors are able to directly regulate transcription upon ligand binding.

Eicosanoids

Straight-chain, 20-carbon polyunsaturated fatty acids that contain an oxygen moiety. Characteristically, eicosanoids are signalling lipids.

Prostaglandins

A subclass of eicosanoids derived from arachidonic acid with a characteristic five-carbon ring. The signalling actions of prostaglandins are highly tissue-specific.

Gluteofemoral depot

A representative, commonly studied human subcutaneous adipose depot. This depot is anatomically located subcutaneously, along the hips, buttocks and thighs.

Omental depot

One of the commonly studied human visceral adipose depots. The omental adipose depot is inside the peritoneum, starts near the stomach and spleen and extends deep into the abdomen.

Panniculus carnosus

Striated muscle anatomically located within or just beneath the superficial fascia of the dermis that controls local movement of the skin. It is present in many lower mammals but absent in humans.

Sarcopenia

The age-related loss of muscle mass.

Metabolic syndrome

A combination of five metabolic risk factors: high blood pressure, elevated fasting blood glucose, hypertriglyceridaemia, decreased serum high-density lipoprotein and increased abdominal adiposity, which collectively increase the risk of heart disease, diabetes and stroke.

Caveolae

Small, flask-like invaginations of plasma membrane that are abundant in many mammalian cell types including adipocytes. They have been implicated in various processes, including endocytosis, signalling, lipid regulation and mechanosensing.

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Ghaben, A.L., Scherer, P.E. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol 20, 242–258 (2019). https://doi.org/10.1038/s41580-018-0093-z

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