Facilitation of breathing by leptin effects in the central nervous system

Abstract

With the global epidemic of obesity, breathing disorders associated with excess body weight have markedly increased. Respiratory dysfunctions caused by obesity were originally attributed to mechanical factors; however, recent studies have suggested a pathophysiological component that involves the central nervous system (CNS) and hormones such as leptin produced by adipocytes as well as other cells. Leptin is suggested to stimulate breathing and leptin deficiency causes an impairment of the chemoreflex, which can be reverted by leptin therapy. This facilitation of the chemoreflex may depend on the action of leptin in the hindbrain areas involved in the respiratory control such as the nucleus of the solitary tract (NTS), a site that receives chemosensory afferents, and the ventral surface of the medulla that includes the retrotrapezoid nucleus (RTN), a central chemosensitive area, and the rostral ventrolateral medulla (RVLM). Although the mechanisms and pathways activated by leptin to facilitate breathing are still not completely clear, evidence suggests that the facilitatory effects of leptin on breathing require the brain melanocortin system, including the POMC–MC4R pathway, a mechanism also activated by leptin to modulate blood pressure. The results of all the studies that have investigated the effect of leptin on breathing suggest that disruption of leptin signalling as caused by obesity‐induced reduction of central leptin function (leptin resistance) is a relevant mechanism that may contribute to respiratory dysfunctions associated with obesity.

Fibro-Adipogenic Remodeling of the Diaphragm in Obesity-Associated Respiratory Dysfunction

“…These findings suggest that hypoventilation in ob/ob mice occurs independent of primary diaphragm compromise. Indeed, leptin is a key regulator of central respiratory control (47), and its administration reverses ventilatory defects observed in ob/ob but not DIO mice (12). We therefore surmise that chronicity of HFD feeding, with potential contribution from dietary content, underlies diaphragm anatomic remodeling and contractile dysfunction not seen in the younger ob/ob mice.…”

Buprenorphine Depresses Respiratory Variability in Obese Mice with Altered Leptin Signaling

“…The present results are consistent with evidence that leptin status rather than obesity causes an impaired ventilatory response to hypercapnia in ob/ob mice. 50…”

A Leptin-Mediated Neural Mechanism Linking Breathing to Metabolism

“…The obesity-associated increased risk of breathing disorders has typically been attributed to mechanical causes, such as fat storage in pharyngeal tissue or decreased neuromuscular tone in the upper airway; however, it has become clear that a blunted central respiratory drive is also critical (Leech et al, 1991). In line with this interpretation, common breathing disorders in individuals with obesity include OHS and sleep-disordered breathing (Bassi et al, 2016;Piper and Grunstein, 2011). The latter includes central sleep apnea, which is a failure of the CNS to generate a respiratory motor output (Eckert et al, 2007).…”

“…Leptin is a pleiotropic hormone principally derived from adipocytes, and recent findings suggest that it may be an important signaling molecule linking ventilation to metabolism. An increase in white adipose tissue increases circulating leptin, which, in turn, induces an increase in energy expenditure (Friedman, 2019) and a parallel increase in breathing (O'Donnell et al, 2000;Bassi et al, 2016;Chang et al, 2013). Leptin-deficient ob/ob mice are obese, hypoventilate with an accompanying increase in arterial PCO 2 (O'Donnell et al, 1999), and have diminished neuromuscular control of the upper airway (Polotsky et al, 2012).…”