Age-dependent obesity and mitochondrial dysfunction

Abstract

Aging is associated with progressive visceral white adipose tissue (WAT) expansion both in human and mouse. Importantly, WAT enlargement is initiated early in life, suggesting that molecular mechanisms underlying age-dependent obesity are activated at early stages of lifetime. Our recent study found that age-dependent obesity was associated with a specific decline in mitochondrial complex IV activity, which leads to reduced fatty acid oxidation and subsequent adipocyte hypertrophy. At the molecular level, global mitochondrial complex IV inhibition was driven by hypoxia-inducible factor-1α (HIF1α)-mediated repression of some of its key subunits, including cytochrome c oxidase 5b (Cox5b). In this commentary, we compare age-dependent WAT responses with those observed in the high fat diet model of extreme obesity. Furthermore, we discuss the potential scenarios that could initiate age-dependent WAT expansion as well as the mechanisms by which HIF1α could be activated in WAT.

Keywords: HIF-1; aging; hypoxia; mitochondrial complex IV; mitochondrial dysfunction; obesity; white adipocytes.

Figure 1.

Role of HIF1α-CIV pathway in age-dependent WAT expansion. White adipocyte enlargement is initiated in early phases during aging. During age-dependent WAT expansion HIF1α is stabilized and promotes CIV dysfunction (CIV) (decreased activity and stability). Adipocytes with a dysfunctional CIV are less oxidative and, therefore, accumulate more lipids allowing further WAT expansion. Age-dependent CIV dysfunction can be alleviated by the ectopic overexpression of the nuclear encoded CIV subunit COX5B in aging mice. Conversely, silencing this CIV subunit in young adipocytes promotes adipocyte enlargement.

Figure 2.

Activation of HIF1α in aging white adipocytes. The figure shows that WAT expansion leads to poor white adipocyte oxygenation (low pO₂), which subsequently promotes HIF1α accumulation. In turn HIF1α accumulation also exacerbates WAT expansion involving mitochondrial complex IV repression (see also Fig. 1). This feed-forward mechanism is indicated with the orange arrow. Moreover, white adipocyte HIF1α accumulation could be promoted - not only by hypoxia in itself - but potentially also by intracellular ROS as well as lipid accumulation (e.g., cholesterol) or other metabolic pathways such as SIRT1 involved in HIF1α activation in other tissues during aging.