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Targeting autophagy in obesity: from pathophysiology to management

Abstract

Obesity poses a severe threat to human health, including the increased prevalence of hypertension, insulin resistance, diabetes mellitus, cancer, inflammation, sleep apnoea and other chronic diseases. Current therapies focus mainly on suppressing caloric intake, but the efficacy of this approach remains poor. A better understanding of the pathophysiology of obesity will be essential for the management of obesity and its complications. Knowledge gained over the past three decades regarding the aetiological mechanisms underpinning obesity has provided a framework that emphasizes energy imbalance and neurohormonal dysregulation, which are tightly regulated by autophagy. Accordingly, there is an emerging interest in the role of autophagy, a conserved homeostatic process for cellular quality control through the disposal and recycling of cellular components, in the maintenance of cellular homeostasis and organ function by selectively ridding cells of potentially toxic proteins, lipids and organelles. Indeed, defects in autophagy homeostasis are implicated in metabolic disorders, including obesity, insulin resistance, diabetes mellitus and atherosclerosis. In this Review, the alterations in autophagy that occur in response to nutrient stress, and how these changes alter the course of obesogenesis and obesity-related complications, are discussed. The potential of pharmacological modulation of autophagy for the management of obesity is also addressed.

Key points

  • Autophagy regulates cellular energy as well as amino acid, glucose and lipid metabolism; conversely, levels of ATP, amino acids, fatty acids and glucose govern autophagy regulation.

  • Autophagy might be either enhanced or suppressed in obesity owing to dyslipidaemia or overnutrition, respectively, and dysregulation of autophagy promotes the onset and development of metabolic disorders.

  • Dysregulation of autophagy exhibits tissue specificity and chronological biphasic changes throughout the course of overnutrition and, consequently, obesogenesis.

  • Loss of autophagy homeostasis in adipose tissue (for example, diminished adipocyte autophagy despite elevated expression of autophagy genes) has unfavourable effects on local and/or global metabolism that promote metabolic disorders.

  • Lifestyle modification (such as exercise and dietary restriction) and pharmacological modulation of autophagy have been proved beneficial for the prevention and treatment of obesity and its complications.

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Fig. 1: Signalling cascades regulating autophagy during nutrient stress and obesity.
Fig. 2: Changes in autophagy in metabolic organs during overnutrition and obesity.

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Acknowledgements

The authors received support in part from the National Key R&D Program of China (2017YFA0506000), the American Diabetes Association (7-13-BS-142-BR, NSFC 81522004, NSFC81570225, NSFC81521001, R01 HL73101-01 A and R01 HL107910-01) and the US Veterans Affairs Merit System (0018). The authors express their sincere apology to those authors whose important work cannot be included owing to space limitations.

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Nature Reviews Endocrinology thanks H. Watada, and the other anonymous reviewers, for their contribution to the peer review of this work.

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Correspondence to Yingmei Zhang or Jun Ren.

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Glossary

Nonselective autophagy

Involves the random uptake of portions of the cytoplasm (cytosol and organelles) in the vacuole and/or lysosome for degradation and recycling.

Cargo-specific autophagy

Selective autophagy characterized by a degradation process that is highly regulated by an autophagy receptor, with sequestration cargo specificity for cytoplasmic contents.

Adipokines

Peptide hormones or cytokines secreted by adipose tissues (including leptin, adiponectin and tumour necrosis factor) that have major roles in multiple biological processes such as glucose and fatty acid metabolism, insulin sensitivity and adipocyte differentiation.

Starvation-induced nascent granule degradation

(SINGD). Refers to the lysosomal degradation of nascent secretory insulin granules when β-cells are subjected to glucose deprivation; this process triggers lysosomal recruitment and activation of mTOR to suppress autophagy.

Golgi membrane-associated degradation

(GOMED). Characterized by the generation of Golgi membrane-associated structures accompanied by proteolysis and is activated when Golgi-to-plasma-membrane anterograde trafficking is disrupted in autophagy-deficient yeast and mammalian cells.

Lipoapoptosis

Apoptosis caused by exposure to an excess of fatty acids.

Metabolic inflexibility

Occurs with an inability to adapt fuel oxidation to fuel availability and is characterized by nutrient overload and increased substrate competition, resulting in impaired fuel switching and energy dysregulation.

Ketogenic diets

High-fat, protein-adequate, low-carbohydrate diets that are used primarily to treat difficult-to-control (refractory) epilepsy in children.

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Zhang, Y., Sowers, J.R. & Ren, J. Targeting autophagy in obesity: from pathophysiology to management. Nat Rev Endocrinol 14, 356–376 (2018). https://doi.org/10.1038/s41574-018-0009-1

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