Role of Leptin in Obesity, Cardiovascular Disease, and Type 2 Diabetes

Abstract

Diabetes mellitus (DM) is a highly prevalent disease worldwide, estimated to affect 1 in every 11 adults; among them, 90-95% of cases are type 2 diabetes mellitus. This is partly attributed to the surge in the prevalence of obesity, which has reached epidemic proportions since 2008. In these patients, cardiovascular (CV) risk stands as the primary cause of morbidity and mortality, placing a substantial burden on healthcare systems due to the potential for macrovascular and microvascular complications. In this context, leptin, an adipocyte-derived hormone, plays a fundamental role. This hormone is essential for regulating the cellular metabolism and energy balance, controlling inflammatory responses, and maintaining CV system homeostasis. Thus, leptin resistance not only contributes to weight gain but may also lead to increased cardiac inflammation, greater fibrosis, hypertension, and impairment of the cardiac metabolism. Understanding the relationship between leptin resistance and CV risk in obese individuals with type 2 DM (T2DM) could improve the management and prevention of this complication. Therefore, in this narrative review, we will discuss the evidence linking leptin with the presence, severity, and/or prognosis of obesity and T2DM regarding CV disease, aiming to shed light on the potential implications for better management and preventive strategies.

Keywords: cardiovascular risk; inflammation; leptin; obesity; type 2 diabetes mellitus.

Figure 1

Signal transduction of leptin receptor. Leptin signaling is based on the autophosphorylation of the leptin receptor, triggering the JAK2-STAT3, IRS/PI3K, MAPK-ERK, and AMPK pathways. JAK, Janus kinase; IRS, insulin receptor substrate; PI3K, phosphatidylinositol 3-kinase; PDE, phosphodiesterase; Akt, protein kinase B; SHP2, tyrosine-protein phosphatase 2 containing SH2; Grb2, growth factor receptor-bound protein 2; MAPK, mitogen-activated protein kinase; PTP, tyrosine-protein phosphatase; STAT, signal transducer and activator of transcription; ERK, extracellular signal-regulated kinase; SOCS3, cytokine signaling 3 suppressor; AMPK, 5′-adenosine monophosphate-activated protein kinase.

Figure 2

Paradoxical effect of leptin: relationship between circulating leptin levels and cardiovascular dysfunction. For proper cardiovascular function, it is essential to maintain circulating leptin levels within a narrow normal range. In conditions of lipodystrophy, resulting from widespread adipose tissue apoptosis or the inability to develop adipose tissue correctly, extremely low levels of circulating leptin promote cardiovascular disorder. Conversely, in diet-induced obesity, hyperleptinemia acts as an important factor in developing cardiovascular dysfunction due to leptin resistance (modified from reference [63]).