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  • Review Article
  • Published:

Targeting adipose tissue in the treatment of obesity-associated diabetes

Nature Reviews Drug Discovery volume 15, pages 639–660 (2016)Cite this article

Subjects

Key Points

  • Adipose tissue regulates many physiological processes, and is essential for handling excess calories.

  • Dysfunction of adipose tissue in obese humans is associated with disrupted metabolic homeostasis and increased risk for metabolic, cardiovascular and chronic inflammatory diseases, such as type 2 diabetes, dyslipidaemia, nonalcoholic fatty liver disease (NAFLD), hypertension, coronary heart disease and stroke.

  • Hence, pharmacological interventions focused on maintaining or improving adipose tissue health form the basis for both prophylactic and therapeutic interventions in metabolic and cardiovascular disease.

  • As an active endocrine organ, some adipocyte-derived secretory proteins and their receptors represent promising pharmacological targets.

  • Although chronic inflammatory processes are key contributors to adipose tissue dysfunction, targeting inflammatory components to achieve metabolic improvements has not proven to be effective to date.

  • Some of the established antidiabetic agents, such as peroxisome proliferator-activated receptor-γ (PPARγ) agonists and glucagon-like peptide 1 receptor (GLP1R) agonists, exert their effects at least partially on adipocytes.

  • Emerging adipose tissue-centric approaches to improve metabolism include reducing fibrosis, reducing hypoxia, enhancing beiging of adipose tissue and identifying key insulin-sensitizing downstream targets of PPARγ, as well as modulating insulin-sensitizing lipids (for example, fatty acid esters of hydroxyl fatty acids (FAHFAs)) or insulin-desensitizing lipids (ceramides).

Abstract

Adipose tissue regulates numerous physiological processes, and its dysfunction in obese humans is associated with disrupted metabolic homeostasis, insulin resistance and type 2 diabetes mellitus (T2DM). Although several US-approved treatments for obesity and T2DM exist, these are limited by adverse effects and a lack of effective long-term glucose control. In this Review, we provide an overview of the role of adipose tissue in metabolic homeostasis and assess emerging novel therapeutic strategies targeting adipose tissue, including adipokine-based strategies, promotion of white adipose tissue beiging as well as reduction of inflammation and fibrosis.

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Figure 1: Crosstalk between white adipose tissue and other tissues in the body.
Figure 2: Metabolically healthy white adipose tissue expansion versus unhealthy pathological expansion during the progression of obesity.
Figure 3: Targeting white adipose tissue for the treatment of obesity-associated diabetes.

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Acknowledgements

The authors would like to thank the rest of the Scherer laboratory for their helpful discussions. The authors were supported by US National Institutes of Health grants R01-DK55758, R01-DK099110 and P01-DK088761 and Cancer Prevention Research Institute of Texas grant RP140412 (to P.E.S.).

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Authors and Affiliations

  1. Department of Internal Medicine, Touchstone Diabetes Center, The University of Texas Southwestern Medical Center,

    Christine M. Kusminski & Philipp E. Scherer

  2. Division of Endocrinology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Perry E. Bickel

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  1. Christine M. Kusminski
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Correspondence to Philipp E. Scherer.

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Lipotoxicity

Impaired cellular functionality (insulin resistance) that is due to exposure to elevated levels of endogenous or exogenous lipids.

Adipokine

An adipocyte-derived secretory product that is either exclusively produced in adipocytes or highly enriched in adipocytes.

Adipogenesis

The process of adipocyte differentiation.

Ceramides and sphingosines

Subclasses of lipids consisting of a serine and a fatty acid. They are implicated in cell death, inflammation and insulin resistance (ceramides) or proliferation and survival (sphingosines).

Extracellular matrix

A fibrotic milieu on the outside of cells that makes up an extracellular scaffold. It can be upregulated in pathological states.

Hypertrophy

Tissue growth through an increase in cell size.

Hyperplasia

Tissue growth through an increase in cell number.

Lipostat

A mechanism by which food intake and energy expenditure are regulated, such that an organism's existing fat mass is maintained.

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Kusminski, C., Bickel, P. & Scherer, P. Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat Rev Drug Discov 15, 639–660 (2016). https://doi.org/10.1038/nrd.2016.75

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