'Metabolically healthy obesity': origins and implications

Abstract

When humans eat more and exercise less, they tend to become obese and unhealthy. The molecular pathways that link obesity to serious diseases like Type 2 diabetes and cardiovascular disease have become a subject of intensive scientific investigation because the exploding prevalence of obesity worldwide represents a grave new threat to the health of hundreds of millions of people. However, obesity is not always destiny. Two important clinical populations have been valuable to understand the mechanisms behind this conundrum: individuals who exhibit metabolic dysfunction, diabetes and elevated cardiovascular disease risk despite a lean body type, and individuals who are relatively protected from these dangers despite significant obesity. Study of this second group of 'metabolically healthy obese' people in particular has been revealing because such individuals exhibit specific, identifiable, anatomic, cellular and molecular features that set them apart from the rest of us who suffer declining health with increasing weight. Here, we examine some of these features, including some mouse models that are informative of mechanism, and suggest hypotheses for further study, including the possibility that genes and pathways of the immune system might offer new diagnostic or therapeutic targets.

Fig 1

A classification model for obese and metabolic phenotypes. A ‘two-by-two’ map of the effects of obesity on health, with two off-diagonal entries.

Fig 2

Three populations of humans or mouse models define risk profiles for obesity-driven metabolic dysfunction. As BMI increases, the risks of T2D and CVD increase, but less steeply for MHO individuals than for the general population. MHO individuals are characterized by less serious increases in central obesity, adipocyte stress and other factors. On the other hand, this model predicts that some individuals will experience greater risk than the general population; these individuals (‘at-risk’) may have predisposition to chronic inflammatory disease, hyper-reactive T cell function, or unresolved co-morbidity such as rheumatoid arthritis, lupus or other autoimmune disorders. ATM; adipose tissue macrophage; BMI, body mass index; CLS, ‘crown-like’ structures; CVD, cardiovascular disease; MHO, metabolically healthy obese; T2D, Type 2 diabetes; WAT, white adipose tissue.

Fig 3

Hypothesis for crosstalk among Brd2-regulated genes. (A) Certain genes are transcriptionally co-repressed by Brd2, such as PPARγ target genes (Wang et al., 2009) and the insulin-1 gene (Wang et al., 2012), whereas other genes are transcriptionally co-activated by Brd2, such as cyclin A (Sinha et al., 2005), which causes cell cycle acceleration and cancer (Greenwald et al., 2004) and pro-inflammatory cytokine genes (Belkina et al., 2010; Belkina et al., forthcoming). (B) Brd2 action permits the MHO phenotype to be interpreted as a coherent transcriptional phenotype of increased adipogenesis (Wang et al., 2009; Belkina and Denis, 2010), reduced inflammation and reduced obesity-associated cancer (Belkina and Denis, 2012; Chadid et al., forthcoming; Denis and Bowen, 2013).