Structure, production and signaling of leptin

Abstract

The cloning of leptin in 1994 was an important milestone in obesity research. In those days obesity was stigmatized as a condition caused by lack of character and self-control. Mutations in either leptin or its receptor were the first single gene mutations found to cause morbid obesity, and it is now appreciated that obesity is caused by a dysregulation of central neuronal circuits. From the first discovery of the leptin deficient obese mouse (ob/ob), to the cloning of leptin (ob aka lep) and leptin receptor (db aka lepr) genes, much has been learned about leptin and its action in the central nervous system. The initial high hopes that leptin would cure obesity were quickly dampened by the discovery that most obese humans have increased leptin levels and develop leptin resistance. Nevertheless, leptin target sites in the brain represent an excellent blueprint for distinct neuronal circuits that control energy homeostasis. A better understanding of the regulation and interconnection of these circuits will further guide and improve the development of safe and effective interventions to treat obesity. This review will highlight our current knowledge about the hormone leptin, its signaling pathways and its central actions to mediate distinct physiological functions.

Keywords: Energy homeostasis; Leptin signaling; Leptin transport; Neuronal circuits.

Fig. 1

Mechanisms of central leptin access. Schematic drawing depicting the border at the level of the median eminence (ME) and arcuate nucleus (ARC) as an example to show different mechanisms of central leptin access. A. Saturable transport of leptin across the blood brain barrier (BBB). B. Direct access of leptin receptor neurons to the circulation via projections close to fenestrated capillaries (perivascular space) in circumventricular organs (CVO’s, e.g. median eminence, area postrema, organum vasculosum). C. Leptin transport via tanycytes into cerebrospinal fluid (CSF) in the ventricular space (e.g. the third ventricle, 3V).

Fig. 2

Leptin signaling pathways and cellular leptin resistance. Schematic drawing of signaling pathways induced via the long form leptin receptor (LepRb). PI3K = phosphatidylinositol-3-kinase; IRS = insulin receptor substrate; JAK2 = janus kinase-2; ER = endoplasmatic reticulum, STAT = signal-transducer-and-activator-of-transcription; SOCS-3 = suppressor-of-cytokine-signaling-3; PTP1B = phosphotyrosine phosphatase 1B; TSC1/2 = tuberous-sclerosis1/2; mTOR = mammalian-target-of-rapamycin; pS6 = phosphorylated ribosomal protein S6; AMPK = AMP-activated protein kinase; ACC = acetyl-CoA carboxylase; SHP-2 = src-homology-2 containing phosphotyrosine phosphatase 2; MAPK = mitogen-activated-protein-kinase.

Fig. 3

Central LepRb expression sites and related neuronal circuits. Leptin acts on diverse central circuits to regulate distinct aspects of energy homeostasis. A–E: Examples of select central circuits that have been studied in more detail for leptin function. Many other LepRb populations (gray areas in top panel) remain to be studied and integrated into a comprehensive picture of energy homeostasis. Specifically higher, cortical brain structures and descending effector pathway have not been well integrated into leptin regulated energy homeostasis. PVN = paraventricular nucleus; ARC = arcuate nucleus; NTS = nucleus of the solitary tract; AgRP = agouti-related-peptide; POMC = proopiomelanocoritin; CeA = amygdala; lPB = lateral parabrachial nucleus; GABA = γ-aminobutyric acid; Glu = glutamate; Nac = nucleus accumbens; LHA = lateral hypothalamic area; VTA = ventral tegmental area; POA = prooptic area; DMH = dorso-medial hypothalamus; RPa = raphe pallidus; SNS = sympathetic nervous system, DMV = dorso-motor complex of vagus; PAG = periaqueductal gray; SCs = sensory cortex; HPC = hippocampus.