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Leptin Function and Regulation

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ABSTRACT

We summarize the biological impact of leptin signaling as well as the molecular and cellular characteristics of leptin action. Our focus is principally in the central nervous system and we describe the properties of the neuronal networks that are mediators of leptin's effects on ingestive behavior, energy balance, and the reproductive system. The molecular targets of leptin's effects are also responsible for the attenuation and termination of the intracellular signal transduction pathway for leptin, providing a clear understanding of the mechanisms leading to leptin resistance or insensitivity. Using the tools of comparative biology, we explore the potential functions of leptin in fish and birds. Based on the highly variable expression of leptin in multiple tissues, a clear lack of expression of leptin in adipocytes in numerous species of fish and birds and an absence of changes of leptin concentrations in blood that are correlated with changes in nutritional status, it is clear that leptin is unlikely to function as a signal for triglyceride stores in nonmammalian species. This comparative survey serves to highlight the unique function of leptin in mammalian biology as a modulator of energy balance, sexual development, and fertility. © 2018 American Physiological Society. Compr Physiol 8:351‐369, 2018.

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Figure 1. Figure 1. Structure of leptin and leptin receptor. Leptin is a 4‐helix bundle cytokine. Two leptin molecules bind to a leptin receptor dimer to activate the JAK2‐STAT3 signaling cascade. JAK2 can be dephosphorylated/deactivated by PTP1B. Three tyrosine residues in the cytoplasmic region of leptin receptor B isoform are targets for phosphorylation by JAK2 and provide docking sites for various signaling molecules. SHP2 and SOCS3 bind to Y985 and act in opposing directions. STAT3 binds to Y1138 and trans‐autophosphorylates itself, leading to phospho‐STAT3 to activate transcriptional targets. pSTAT3 also induces SOCS3, leading to autotermination of the LEPR signal and a potential mechanism of leptin receptor desensitization.
Figure 2. Figure 2. Types and locations of leptin receptor bearing neurons involved in regulating metabolism, feeding and reproduction. Leptin receptors within the PVN (paraventricular nucleus) are expressed in TRH (thyrotropin releasing hormone) and oxytocin neurons. Within the ARC (arcuate nucleus), at least three types of neurons are critical to leptin action. The two types of melanocortinergic neurons, POMC neurons and AGRP/NPY/GABA neurons, act in opposing directions to control feeding, energy balance, and fertility. Within the VMN (ventromedial nucleus), the SF1 neurons are critical for feeding and glucose control. Within the ARC and the PMV (ventral premammilary nucleus), two types of neurons the NOS and KNDY (kisspeptin/neuromedin B/dynorphin) neurons send projections to control the activity and secretion of GnRH neurons. Within the LHA (lateral hypothalamic area), there are LEPR‐B expressing neurons that remain to be chemically identified and whose roles remain to be defined. There are also GABAergic LEPR‐B expressing neurons whose locations remain undefined that contribute to a majority of leptin's actions on feeding and energy balance.
Figure 3. Figure 3. Alignment of fish and avian leptins to human leptin. The amino acids in the predicted alpha helices are shown in bold. Identical amino acids are highlighted in yellow whereas homologous amino acids are highlighted in light blue. The conserved cysteines are indicated with asterisks.


Figure 1. Structure of leptin and leptin receptor. Leptin is a 4‐helix bundle cytokine. Two leptin molecules bind to a leptin receptor dimer to activate the JAK2‐STAT3 signaling cascade. JAK2 can be dephosphorylated/deactivated by PTP1B. Three tyrosine residues in the cytoplasmic region of leptin receptor B isoform are targets for phosphorylation by JAK2 and provide docking sites for various signaling molecules. SHP2 and SOCS3 bind to Y985 and act in opposing directions. STAT3 binds to Y1138 and trans‐autophosphorylates itself, leading to phospho‐STAT3 to activate transcriptional targets. pSTAT3 also induces SOCS3, leading to autotermination of the LEPR signal and a potential mechanism of leptin receptor desensitization.


Figure 2. Types and locations of leptin receptor bearing neurons involved in regulating metabolism, feeding and reproduction. Leptin receptors within the PVN (paraventricular nucleus) are expressed in TRH (thyrotropin releasing hormone) and oxytocin neurons. Within the ARC (arcuate nucleus), at least three types of neurons are critical to leptin action. The two types of melanocortinergic neurons, POMC neurons and AGRP/NPY/GABA neurons, act in opposing directions to control feeding, energy balance, and fertility. Within the VMN (ventromedial nucleus), the SF1 neurons are critical for feeding and glucose control. Within the ARC and the PMV (ventral premammilary nucleus), two types of neurons the NOS and KNDY (kisspeptin/neuromedin B/dynorphin) neurons send projections to control the activity and secretion of GnRH neurons. Within the LHA (lateral hypothalamic area), there are LEPR‐B expressing neurons that remain to be chemically identified and whose roles remain to be defined. There are also GABAergic LEPR‐B expressing neurons whose locations remain undefined that contribute to a majority of leptin's actions on feeding and energy balance.


Figure 3. Alignment of fish and avian leptins to human leptin. The amino acids in the predicted alpha helices are shown in bold. Identical amino acids are highlighted in yellow whereas homologous amino acids are highlighted in light blue. The conserved cysteines are indicated with asterisks.
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Teaching Material

Y. Zhang, S. Chua Jr. Leptin Function and Regulation. Compr Physiol 8: 2018, 351-369.

Didactic Synopsis

Major Teaching Points:

  1. Leptin functions as a circulating signal for triglyceride stores in adipose tissue.
  2. Leptin receptors within the central nervous system control most of the effects of leptin on ingestive behavior, substrate utilization in peripheral organs, puberty, and reproductive biology.
  3. The neuronal network of leptin responsive neurons functions as a distributed network utilizing discrete neurotransmitters including numerous fast neurotransmitters and neuropeptides.
  4. Leptin binding to the JAK2-STAT3 signaling competent leptin receptor isoform leads to the induction of SOCS3 that terminates leptin signaling by terminating JAK2 activity through ubiqutin-mediated degradation of JAK2. Phosphatases, specifically PTP1B, also dephosphorylate JAK2.
  5. Elevation of leptin concentrations in blood caused by increased adiposity leads to leptin resistance, presumably via enhanced or persistent activation of SOCS3.
  6. Leptin genes have been found in mammal, reptiles, birds, amphibians, and bony fishes, although expression of leptin is not primarily in adipocytes, precluding leptin being a critical signal of triglyceride stores for adipose tissue in nonmammalian species.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: Structure of leptin and leptin receptor. Leptin is a 4-helix bundle cytokine. Two leptin molecules bind to a leptin receptor dimer to activate the JAK2-STAT3 signaling cascade. JAK2 can be dephosphorylated/deactivated by PTP1B. Three tyrosine residues in the cytoplasmic region of leptin receptor B isoform are targets for phosphorylation by JAK2 and provide docking sites for various signaling molecules. SHP2 and SOCS3 bind to Y985 and act in opposing directions. STAT3 binds to Y1138 and trans-autophosphorylates itself, leading to phospho-STAT3 to activate transcriptional targets. pSTAT3 also induces SOCS3, leading to autotermination of the LEPR signal and a potential mechanism of leptin receptor desensitization.

Figure 2. Teaching points: Types and locations of leptin receptor bearing neurons involved in regulating metabolism, feeding, and reproduction. Leptin receptors within the PVN (paraventricular nucleus) are expressed in TRH (thyrotropin releasing hormone) and oxytocin neurons. Within the ARC (arcuate nucleus), at least three types of neurons are critical to leptin action. The two types of melanocortinergic neurons, POMC (pro-opiomelanocortin) neurons and AGRP (agouti-gene-related peptide)/NPY (neuropeptide Y)/GABA neurons, act in opposing directions to control feeding, energy balance, and fertility. Within the VMN (ventromedial nucleus), the SF1 (steroidogenic factor 1) neurons are critical for feeding and glucose control. Within the ARC and the PMV (ventral premammilary nucleus), two types of neurons the NOS (nitric oxide synthase) and KNDY (kisspeptin/neuromedin B/dynorphin) neurons send projections to control the activity and secretion of GnRH neurons. Within the LHA (lateral hypothalamic area), there are LEPR-B expressing neurons that remain to be chemically identified and whose roles remain to be defined. There are also GABAergic LEPR-B expressing neurons whose locations remain undefined that contribute to a majority of leptin's actions on feeding and energy balance.

Figure 3. Teaching points: Alignment of fish and avian leptins to human leptin. The amino acids in the predicted alpha helices are shown in bold. Identical amino acids are highlighted in yellow whereas homologous amino acids are highlighted in light blue. The conserved cysteines are indicated with asterisks.

 


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How to Cite

Yiying Zhang, Streamson Chua. Leptin Function and Regulation. Compr Physiol 2017, 8: 351-369. doi: 10.1002/cphy.c160041