Leptin resistance: a possible interface of inflammation and metabolism in obesity-related cardiovascular disease

Abstract

Leptin is an adipocyte-derived hormone and cytokine that regulates energy balance through a wide range of functions, including several that are important to cardiovascular health. Increased circulating leptin, a marker of leptin resistance, is common in obesity and independently associated with insulin resistance and cardiovascular disease (CVD) in humans. The mechanisms of leptin resistance include genetic mutation, leptin self-regulation, limited tissue access, and cellular or circulating molecular regulation. Evidence suggests that central leptin resistance causes obesity and that obesity-induced leptin resistance injures numerous peripheral tissues, including liver, pancreas, platelets, vasculature, and myocardium. This metabolic- and inflammatory-mediated injury may result from either resistance to leptin's action in selective tissues, or excess leptin action from adiposity-associated hyperleptinemia. In this sense, the term "leptin resistance" encompasses a complex pathophysiological phenomenon. The leptin axis has functional interactions with elements of metabolism, such as insulin, and inflammation, including mediators of innate immunity, such as interleukin-6. Leptin is even purported to physically interact with C-reactive protein, resulting in leptin resistance, which is particularly intriguing, given C-reactive protein's well-studied relationship to cardiovascular disease. Given that plasma levels of leptin and inflammatory markers are correlated and also predict cardiovascular risk, it is conceivable that part of this risk may be mediated through leptin resistance-related insulin resistance, chronic inflammation, type II diabetes, hypertension, atherothrombosis, and myocardial injury. Leptin resistance and its interactions with metabolic and inflammatory factors, therefore, represent potential novel diagnostic and therapeutic targets in obesity-related cardiovascular disease.

Figure 1. Mechanisms of leptin resistance

CNS = central nervous system; Ob = leptin gene; Ob-R = leptin receptor gene; PTP1B = protein tyrosine phosphatase 1B; SLR = soluble leptin receptor; SLIPs = serum leptin-interacting proteins; SOCS3 = suppressor-of cytokine-signaling-3.

Figure 2. Theoretical cellular and molecular mechanisms of leptin pathophysiology

(A) In leptin resistant tissue (e.g., hypothalamic cell illustrated), serum leptin-interacting proteins (SLIPs) and soluble leptin receptor (SLR) may bind circulating adipose-secreted leptin and inhibit its action. Free leptin engages the long form of its receptor (Ob-Rb), which homodimerizes. Intracellularly, activated janus kinase 2 (JAK2) phosphorylates a specific tyrosine docking site (Tyr1138) on Ob-Rb. Signal transduction and translation protein 3 (STAT3) recognizes and binds to activated Tyr1138 via its src homology 2 (SH2) domain. The Ob-Rb/JAK2 complex activates STAT3, which homodimerizes, then translocates to the nucleus to modulate gene transcription. STAT3 upregulates expression of suppressor-of cytokine-signaling-3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B), which block JAK2 phosphorylation. It is thought that central leptin resistance promotes obesity, driving greater hyperleptinemia. (B) In non-leptin resistant tissue (e.g., immune cell illustrated) exposed to hyperleptinemia, Ob-Rb may signal excessively through multiple signaling pathways, including JAK/STAT, insulin receptor substrate-2/phosphatidylinositol 3-kinase (IRS-2/PI3K), and nitric oxide that may ultimately promote cardiovascular disease (CVD) through tissue specific mechanisms.

Figure 3. Overview of leptin resistance and hyperleptinemia in obesity-related cardiovascular disease

A leptin resistant/hyperleptinemic state is a putative link between obesity and diverse vascular and myocardial injury via direct effects or intermediary disorders. Site of effect (central versus peripheral) is depicted.