Leptin signaling and leptin resistance

Abstract

With the prevalence of obesity and associated comorbidities, studies aimed at revealing mechanisms that regulate energy homeostasis have gained increasing interest. In 1994, the cloning of leptin was a milestone in metabolic research. As an adipocytokine, leptin governs food intake and energy homeostasis through leptin receptors (LepR) in the brain. The failure of increased leptin levels to suppress feeding and elevate energy expenditure is referred to as leptin resistance, which encompasses complex pathophysiological processes. Within the brain, LepR-expressing neurons are distributed in hypothalamus and other brain areas, and each population of the LepR-expressing neurons may mediate particular aspects of leptin effects. In LepR-expressing neurons, the binding of leptin to LepR initiates multiple signaling cascades including janus kinase (JAK)-signal transducers and activators of transcription (STAT) phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), extracellular regulated protein kinase (ERK), and AMP-activated protein kinase (AMPK) signaling, etc., mediating leptin actions. These findings place leptin at the intersection of metabolic and neuroendocrine regulations, and render leptin a key target for treating obesity and associated comorbidities. This review highlights the main discoveries that shaped the field of leptin for better understanding of the mechanism governing metabolic homeostasis, and guides the development of safe and effective interventions to treat obesity and associated diseases.

Keywords: leptin; leptin cellular pathways; leptin neural pathways; leptin resistance.

Figure 1:

Brain nucleus and neural pathways underlying leptin function. Orange background: regions of neurons responsive to direct leptin stimulation; red color text: regions of neurons activated by leptin; green color text: regions of neurons inactivated by leptin. ARC, arcuate nucleus; AgRP, agouti-related peptide; CCK, cholecystokinin; CeA, central nucleus of amygdala; DMH, dorsomedial hypothalamus; GLP-1, glucagon-like peptide-1; LHA, lateral hypothalamic area; MCH, melanin concentrating hormone; NAc, nucleus accumbens; NTS, nucleus tractus solitaries; POMC, proopiomelanocortin; PBN, parabrachial nucleus; POA, preoptic area; PVH, paraventricular nucleus; PAG, periaqueductal grey matter; RPa, raphe pallidus; ROb, raphe obscurus; RMg, raphe magnus; VMH, ventromedial hypothalamic nucleus; VTA, ventral tegmental area.

Figure 2:

Cellular pathways underlying leptin function. : Activating; : Inhibiting; : Translocation. ACC, acetyl-CoA carboxylase; AgRP, agouti-related peptide; AKT, protein kinase B; AMP, adenosine monophosphate; AMPK, adenosine monophosphate activated protein kinase; ATP, adenosine-5′-triphosphate; CREB, cAMP response element-binding protein; FoxO1, forkhead box protein O1; HDAC5, histone deacetylases 5; HSP60, heat shock protein: 60; IRS, insuline receptor substrate; JAK2, janus kinases 2; LCFA-CoA, long chain fatty acid-coenzyme A; LepR, leptin receptor; MAGEL2, melanoma antigen-like gene 2; MAPKs, mitogen-activated protein kinases; mTOR, mammalian target of rapamycin; NPY, neuropeptide Y; PDE3B, phosphodiesterase 3B; PI3K, phosphatidylinositol 3-OH kinase; PIP3, phosphatidylinositol-3,4,5-trisphosphate; POMC, proopiomelanocortin; PTP1B, protein tyrosine phosphatase 1B; ROCK1, Rho-kinasel; S6K, S6 kinase; SF1, steroidogenic factor 1; SH2B1, Src-homology-2 B adaptor protein-1; SHP2, SH2-containing protein tyrosine phosphatase 2; SIRT1, NAD⁺-dependent deacetylase sirtuin 1; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3; STAT5, signal transducer and activator of transcription 5; TCPTP, T cell protein tyrosine phosphatase.