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  • Review Article
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Convertible visceral fat as a therapeutic target to curb obesity

Nature Reviews Drug Discovery volume 15, pages 405–424 (2016)Cite this article

Subjects

Key Points

  • Obesity is a pathological enlargement of the adipose organ; this process involves the whitening and functional impairment of thermogenic brown adipose tissue and the inflammation of hypertrophied adipose depots.

  • The occurrence of these two phenomena at visceral fat sites causes the most dangerous outcomes of obesity, including type 2 diabetes mellitus, dyslipidaemia, non-alcoholic fatty liver disease, cardiovascular disease and even some cancers. Visceral adipocytes are particularly vulnerable to lipid overload, possibly because of their developmental route and the reduced size at which they die, thereby promoting inflammation.

  • Human and rodent visceral adipocytes exhibit remarkable cell plasticity. Indeed, such cells are particularly prone to re-convert into metabolically healthy, energy-dissipating adipocytes.

  • Molecular targets and pathways that are involved in white-to-brown visceral adipocyte transdifferentiation are potential novel targets of anti-obesity drugs.

  • Even the early steps of white-to-brown adipocyte transdifferentiation, which include adipocyte size reduction and mitochondriogenesis, could promote a healthy adipose phenotype and achieve effective therapeutic outcomes.

Abstract

New therapeutic and preventative strategies are needed to address the growing obesity epidemic. In animal models, brown adipose tissue activation and the associated heat produced contribute to countering obesity and the accompanying metabolic abnormalities. Adult humans also have functional brown fat. Here, we present and discuss the concepts of murine and human white adipose tissue plasticity and the transdifferentiation of white adipocytes into brown adipocytes. Human visceral adipocytes — which are crucial contributors to the burden of obesity and its complications — are particularly susceptible to such transdifferentiation. Therefore, we propose that this process should be a focus of anti-obesity research. Approved drugs that have browning properties as well as future drugs that target molecular pathways involved in white-to-brown visceral adipocyte transdifferentiation may provide new avenues for obesity therapy.

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Figure 1: The adipose organ is highly plastic in both rodents and humans.
Figure 2: Cellular complexity of the adipose organ.
Figure 3: Potential β3-adrenoceptor-dependent molecular mechanisms driving white-to-brown adipocyte transdifferentiation.

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Acknowledgements

S.C. is supported by grants from the Italian Ministry of Education, University and Research (PRIN 2010–11) and the European Community (EU FP7 project DIABAT, HEALTH- F2-2011-278373). The authors thank M. Boscaro (University of Padua, Italy) for critically reading the manuscript and E. Nisoli (University of Milan, Italy) for the expert review of tables 1 and 2.

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Authors and Affiliations

  1. Department of Experimental and Clinical Medicine, University of Ancona (Università Politecnica delle Marche), Via Tronto, 10/A, Ancona, 60020, Italy

    Antonio Giordano & Saverio Cinti

  2. Department of Public Health Experimental and Forensic Medicine, University of Pavia, Pavia, 27100, Italy

    Andrea Frontini

  3. Center of Obesity, University of Ancona (Università Politecnica delle Marche)-United Hospitals, Ancona, 60020, Italy

    Saverio Cinti

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  1. Antonio Giordano
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  2. Andrea Frontini
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  3. Saverio Cinti
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Correspondence to Saverio Cinti.

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PowerPoint slides

Glossary

Brown adipose tissue

(BAT). The mammalian tissue composed of either brown or beige/brite adipocytes. BAT is involved in non-shivering thermogenesis to maintain body temperature homeostasis.

White-to-brown transdifferentiation

The direct and progressive conversion of fully differentiated white adipocytes into heat-producing brown adipocytes without passing through an undifferentiated, stem-like state.

Endothelial–mesenchymal transition

The process by which endothelial cells lose their cell–cell adhesion and gain migratory properties to differentiate into a mesenchymal cell type

Visceral fat

The fat found in the trunk in close contact with the viscera.

Pyroptosis

A highly inflammatory type of cell death involving caspase 1 activation, DNA fragmentation, cell membrane pore formation and cellular lysis.

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Giordano, A., Frontini, A. & Cinti, S. Convertible visceral fat as a therapeutic target to curb obesity. Nat Rev Drug Discov 15, 405–424 (2016). https://doi.org/10.1038/nrd.2016.31

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