Obesity, estrogens and adipose tissue dysfunction - implications for pulmonary arterial hypertension

Abstract

Obesity is a prevalent global public health issue characterized by excess body fat. Adipose tissue is now recognized as an important endocrine organ releasing an abundance of bioactive adipokines including, but not limited to, leptin, adiponectin and resistin. Obesity is a common comorbidity amongst pulmonary arterial hypertension patients, with 30% to 40% reported as obese, independent of other comorbidities associated with pulmonary arterial hypertension (e.g. obstructive sleep apnoea). An 'obesity paradox' has been observed, where obesity has been associated with subclinical right ventricular dysfunction but paradoxically may confer a protective effect on right ventricular function once pulmonary hypertension develops. Obesity and pulmonary arterial hypertension share multiple pathophysiological mechanisms including inflammation, oxidative stress, elevated leptin (proinflammatory) and reduced adiponectin (anti-inflammatory). The female prevalence of pulmonary arterial hypertension has instigated the hypothesis that estrogens may play a causative role in its development. Adipose tissue, a major site for storage and metabolism of sex steroids, is the primary source of estrogens and circulating estrogens levels which are elevated in postmenopausal women and men with pulmonary arterial hypertension. This review discusses the functions of adipose tissue in both health and obesity and the links between obesity and pulmonary arterial hypertension. Shared pathophysiological mechanisms and the contribution of specific fat depots, metabolic and sex-dependent differences are discussed.

Keywords: aromatase; metabolic syndrome; sex differences.

Fig. 1.

Adipose tissue dysfunction in obesity. Insufficient storage capacity of adipocytes in obesity results in systemic inflammation, increased lipolysis, hypoxia and altered adipokine secretion. These factors result in the development of insulin resistance and metabolic syndrome which further impairs adipose tissue function and contributes to obesity-related diseases. CRP: C-reactive protein; ECM: extracellular matrix; FFAs: free fatty acids; HIF1α: hypoxia-inducible factor-1; IL-6: interleukin-6; TNFα: tumour necrosis factor-α.

Fig. 2.

Local production of estrogens in human adipose tissue from circulating precursors. DHEA: dehydroepiandrosterone; DHEA-S: DHEA sulfate; 17β-HSD: 17β-hydroxysteroid dehydrogenase; 3β-HSD: 3β-hydroxysteroid dehydrogenase.

Fig. 3.

Mechanisms mediating the upregulation of aromatase and estrogen (E2) production in adipose tissue. Increased local inflammation due to macrophage infiltration in obese adipose tissue results in the production of inflammatory mediators known to induce the transcriptional upregulation of aromatase resulting in increased E2 production. COX2: cyclooxygenase-2; E2: estrogen; IL-6: interleukin-6; PGE2: prostaglandin E2; TNFα: tumour necrosis factor-α.

Fig. 4.

Estrogen metabolism. Estrone (E1) and estradiol (E2) are synthesized by aromatase. Hydroxylation of E1 and E2 occurs at C2, C4 and C16 positions by cytochrome P450 enzymes (the most prominent being CYP1A2 and CYP1B1 promoting beneficial and detrimental hydroxylation, respectively) resulting in the formation of 16α-hydroxyestrogens, 2-hydroxyestogens and 4-hydroxyestrogens by cytochrome P450 enzymes. The 2- and 4- hydroxyestrogens are converted to 2- and 4-methoxyestrogens via COMT. All E1 and E2 metabolites are maintained in equilibrium by 17β-HSD1 and 17β-HSD2 enzymes. PAH: pulmonary arterial hypertension; COMT: catechol-O-methyltransferase; 17β-HSD: 17β-hydroxysteroid dehydrogenase; 16OHE1: 16α-hydroxyestrone; 16OHE2: 16α-hydroxyestradiol; 2OHE1: 2-hydroxyestrone; 2OHE2: 2-hydroxyestradiol; 4OHE1: 4-hydroxyestrone; 4OHE2: 4-hydroxyestradiol; 2MeOE1: 2-methoxyestrone; 2MeOE2: 2-methoxyestradiol; 4MeOE1: 4-methoxyestrone; 4MeOE2: 4-methoxyestradiol.

Fig. 5.

Changes in estrogen metabolism in adipose tissue and its contribution to the development of obesity-related PAH. Obesity causes an increase in the expression of aromatase and CYP1B1 in adipose tissue resulting in the increased production of estrogen (E2) and its metabolite 16OHE1. In particular, 16OHE1 induces proliferation of PASMCs and contributes to pulmonary vascular remodelling in PAH. CYP1B1 is also associated with insulin resistance, another underlying pathology linked with PAH. PAH: pulmonary arterial hypertension; 16OHE1: 16α-hydroxyestrone; PASMCs: pulmonary artery smooth muscle cells.