History and future of leptin: Discovery, regulation and signaling

Abstract

The cloning of leptin 30 years ago in 1994 was an important milestone in obesity research. Prior to the discovery of leptin, 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 severe obesity, and it is now recognized that obesity is caused mostly by a dysregulation of central neuronal circuits. Since the discovery of the leptin-deficient obese mouse (ob/ob) the cloning of leptin (ob aka lep) and leptin receptor (db aka lepr) genes, we have learned much about leptin and its action in the central nervous system. The first hope that leptin would cure obesity was quickly dampened because humans with obesity have increased leptin levels and develop leptin resistance. Nevertheless, leptin target sites in the brain represent an excellent blueprint to understand how neuronal circuits control energy homeostasis. Our expanding understanding of leptin function, interconnection of leptin signaling with other systems and impact on distinct physiological functions continues to guide and improve the development of safe and effective interventions to treat metabolic illnesses. This review highlights past concepts and current emerging concepts of the hormone leptin, leptin receptor signaling pathways and central targets to mediate distinct physiological functions.

Keywords: Energy expenditure; Feeding; Glucose homeostasis; Leptin receptor; Leptin transport; Neuronal circuits; Reward.

Figure 1:. Leptin promoter and environmental modulator of leptin gene expression

A schematic of the leptin gene locus is shown to illustrate that beyond the classic promoter and leptin gene components, more recent findings identified leptin enhancer sites (LE1 and LE2) and a non-coding sequence (IncOb) upstream of the leptin promoter sites that forms a hairpin RNA structure and interacts with the leptin promoter. The leptin promoter is the key to understanding how leptin production and release is restricted to adipose tissue, reflects body adiposity in the long-term, while allowing acute physiological adaptations (fasting). This is a surprisingly understudied area, despite its importance to understand the role of fluctuating leptin levels in energy homeostasis.

Figure 2:. 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 leptin access to the circulation via projections into circumventricular organs (CVO’s, e.g., median eminence, area postrema, organum vasculosum) that lack a BBB and show fenestrated blood vessels for open exchange into and from the circulation. The neuronal processes that contact fenestrated blood vessels in the CVO are stabilized by NG2 glia cells at least in the median eminence. C. Leptin is also transported by tanycytes (specialized glia-like cells) into the cerebrospinal fluid (CSF). Tanycytes span from the median eminence into the CSF of the third ventricle (3V).

Figure 3:. Leptin signaling pathways and cellular leptin resistance.

Schematic drawing of leptin signaling pathways via the long form leptin receptor (Lepr-b). The right side depicts phosphorylation sites (P) on tyrosine residues (Y) and their main signaling axis through STAT signaling and transcriptional regulation, that is also the source of negative feedback proteins (SOCS3, PTP1B). Lepr signaling levels via PY1138 and pSTAT3 nicely reflect the leptin sensitivity. In addition, Lepr acetylation also profoundly sensitized leptin signaling by stabilizing Lepr-phosphorylation. On the left side a variety of other signaling mechanisms are depicted that either directly interact with Lepr signaling via serin phosphorylation of JAK2 and subsequent IRS and PI3K signaling or other mechanisms that interact with leptin induced transcription. PI3K = phosphatidylinositol-3-kinase; IRS = insulin receptor substrate; JAK2 = janus kinase-2; ER = endoplasmic 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 = mitogene-activated-protein-kinase, HDAC6 =histone deacetylase 6

Figure 4:. Central Lepr-b expression sites and related neuronal circuits to regulate energy homeostasis.

A-E. Depiction of Lepr circuits that contribute directly to distinct aspects of energy homeostasis. These are examples of central circuits that have been studied in more detail for leptin function. Other Lepr populations (grey in top panel) remain to be studied and integrated into a holistic picture of energy homeostasis. Specifically higher, cortical brain structures and descending effector pathway have not been well integrated into leptin regulated energy homeostasis. Note, that the depicted pathways are interconnected at several levels, some of these interconnections were omitted to highlight distinct circuitries. Thus, the schematic does not intend to show a complete map of possible interconnections. PVN = paraventricular nucleus; ARC = arcuate nucleus; NTS = nucleus of the solitary tract; AgRP = agouti-related-peptide; POMC = proopiomelanocortin; CeA = amygdala; PB =parabrachial nucleus; GABA = ɣ-aminobutyric acid; Glu = glutamate; NAc = nucleus accumbens; LHA = lateral hypothalamic area; VTA = ventral tegmental area; POA = preoptic area; DMH = dorso-medial hypothalamus; RPa = raphe pallidus; SNS = sympathetic nervous system, DMV = dorso-motor complex of vagus; PAG = periaqueductal grey; SCx = sensory cortex; HPC = hippocampus

Figure 5:. Leptin and integration into autonomic circuits.

A. Parasympathetic axis with Lepr expressing neurons in the NTS that receive vagal sensory information, but Lepr expressing neurons are also directly found in vagal-sensory neurons in the nodose ganglion. Those vagal-sensory Lepr neurons may directly sense leptin released from the stomach mucosa or circulating leptin may reach Lepr-expressing NTS neurons by transport or by projections outside the BBB (area postrema). These signals are further mediated to the hypothalamus and hypothalamic signals can modulate parasympathetic outputs in the DMV. B. The sympathetic nervous system affects leptin production in adipocytes by adrenergic stimulation of β₃-adrenergic receptors. Leptin acts directly as interoceptive signal to communicate directly with hypothalamic neurons. These Lepr neurons are often sensitive to a variety of environmental signals and thus take part in the integration of these signals. There is no consensus on how leptin levels are reflective of the whole-body system and is an important roadblock to understanding dynamic changes in homeostatic levels (body weight, glucose levels, blood pressure, body temperature). Hyp= hypothalamus; Glp1= glucagon like peptide 1; CCK = cholecystokinin; NTS= nucleus of the solitary tract; DMV = dorso-motor complex of vagus; DRG=dorsal root ganglia; StG = stellate ganglion; T1–12=thoracic sympathetic ganglia 1–12; L1 = lumbar sympathetic ganglia 1