Mechanisms and treatment of obesity-related hypertension-Part 1: Mechanisms

Abstract

The prevalence of obesity has tripled over the past five decades. Obesity, especially visceral obesity, is closely related to hypertension, increasing the risk of primary (essential) hypertension by 65%-75%. Hypertension is a major risk factor for cardiovascular disease, the leading cause of death worldwide, and its prevalence is rapidly increasing following the pandemic rise in obesity. Although the causal relationship between obesity and high blood pressure (BP) is well established, the detailed mechanisms for such association are still under research. For more than 30 years sympathetic nervous system (SNS) and kidney sodium reabsorption activation, secondary to insulin resistance and compensatory hyperinsulinemia, have been considered as primary mediators of elevated BP in obesity. However, experimental and clinical data show that severe insulin resistance and hyperinsulinemia can occur in the absence of elevated BP, challenging the causal relationship between insulin resistance and hyperinsulinemia as the key factor linking obesity to hypertension. The purpose of Part 1 of this review is to summarize the available data on recently emerging mechanisms believed to contribute to obesity-related hypertension through increased sodium reabsorption and volume expansion, such as: physical compression of the kidney by perirenal/intrarenal fat and overactivation of the systemic/renal SNS and the renin-angiotensin-aldosterone system. The role of hyperleptinemia, impaired chemoreceptor and baroreceptor reflexes, and increased perivascular fat is also discussed. Specifically targeting these mechanisms may pave the way for a new therapeutic intervention in the treatment of obesity-related hypertension in the context of 'precision medicine' principles, which will be discussed in Part 2.

Keywords: hypertension; leptin; obesity; renin–angiotensin–aldosterone system; sympathetic nervous system.

Graphical Abstract

Figure 1:

Putative mechanisms of obesity-related hypertension. BAT, baroreceptor activation therapy; CV, cardiovascular; MSNA, muscle sympathetic nerve activity; NP, natriuretic peptide; POMC-MC3/4R, pro-opiomelanocortin-melanocortin receptors; RDN, renal denervation; ROS, reactive oxygen species; RSNA, renal sympathetic nerve activity.

Figure 2:

Mechanisms of hyperfiltration in obesity. TGF, tubule-glomerular feedback; RPF, renal plasma flow; GFR, glomerular filtration rate, Na⁺, sodium.

Figure 3:

Hypothetical model of leptin sympatho-excitatory action and its synergism with AngII in the arcuate nucleus. LR, leptin receptor; PVN, paraventricular nucleus; RSNS, renal sympathetic nervous system; TH, tyrosine hydroxylase; VAT, visceral adipose tissue; Y₁R, neuropeptide Y receptor.

Figure 4:

Hypothetical model of the morpho-functional changes in cardiorenal, vascular and visceral adipose tissue under MR overactivation and their association with hypertension. ECs, endothelial cells; VAT, visceral adipose tissue; VSMCs, vascular smooth muscle cells.