1870-P: Glucagon-Receptor Signaling Reverses Hepatic Steatosis Independent of Leptin Receptor Expression

Abstract Glucagon (GCG) is an essential regulator of glucose and lipid metabolism that also promotes weight loss. We have shown that glucagon-receptor (GCGR) signaling increases fatty acid oxidation (FAOx) in primary hepatocytes and reduces liver triglycerides in diet-induced obese (DIO) mice; however, the mechanisms underlying this aspect of GCG biology remains unclear. Investigation of hepatic GCGR targets elucidated a potent and previously unknown induction of leptin receptor (Lepr) expression. Liver leptin signaling is known to increase FAOx and decrease liver triglycerides, similar to glucagon action. Therefore, we hypothesized that glucagon increases hepatic LEPR, which is necessary for glucagon-mediated reversal of hepatic steatosis. Eight-week-old control and liver-specific LEPR-deficient mice (LeprΔliver) were placed on a high-fat diet for 12 weeks and then treated with a selective GCGR agonist (IUB288) for 14 days. Liver triglycerides and gene expression were assessed in liver tissue homogenates. Administration of IUB288 in both lean and DIO mice increased hepatic Lepr isoforms a-e in acute (4 hours) and chronic (72 hours,16 days) (P < 0.05) settings. LeprΔliver mice displayed increased hepatic triglycerides on a chow diet alone (P < 0.05), which persisted in a DIO state (P < 0.001), with no differences in body weight or composition. Surprisingly, chronic administration of IUB288 in DIO control and LeprΔliver mice reduced liver triglycerides regardless of genotype (P < 0.05). Together, these data suggest that GCGR activation induces hepatic Lepr expression and, although hepatic glucagon and leptin signaling have similar liver lipid targets, these appear to be 2 distinct pathways.

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Abstract 5525: Leptin Receptor Signaling Pathways are protective Against Atherosclerosis in a Mouse Model of Obesity and Hyperlipidemia

Circulation ◽

10.1161/circ.118.suppl_18.s_567-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Wei Luo ◽

Yuechun Shen ◽

Kevin Wickenheiser ◽

Miina Öhman ◽

Martin Myers ◽

...

Keyword(s):

Mouse Model ◽

Signaling Pathways ◽

Hepatic Steatosis ◽

Leptin Receptor ◽

Heart Association ◽

Receptor Expression ◽

Metabolic Effects ◽

Receptor Signaling ◽

Vascular Effects ◽

Adipose Inflammation

Leptin is an adipocyte-derived hormone that has been shown to exert both beneficial metabolic effects and potentially adverse vascular effects in preclinical studies. To determine the effects of leptin receptor signaling pathways on atherosclerosis in the setting of obesity and hyperlipidemia, mice were generated with deficiency of apolipoprotein E ( ApoE −/− ) and either wild-type leptin receptor expression ( Lepr +/+ ,ApoE −/− ), mutant leptin receptor expression defective in all leptin receptor signaling pathways ( Lepr db/db ,ApoE −/− ), or mutant leptin receptor with selective deficiency of leptin receptor-STAT3 signaling ( Lepr s/s ,ApoE −/− ). At 27 weeks of age, which included 7 weeks on western chow, Lepr db/db ,ApoE −/− developed increased weight (61.9 ±3.5 vs 28±2.5, p<0.001), increased leptin (127.8±34 vs 24±12.5, p<0.003), increased NEFAC (2.4±0.75 vs 0.65±0.11, p<0.05) and more atherosclerosis (13.9±1.7 vs 4.3±0.9, p=0.001) than Lepr +/+ ,ApoE −/− mice. In contrast, despite similar obesity and hyperlipidemia to Lepr db/db ,ApoE −/− mice, the atherosclerosis in Lepr s/s ,ApoE −/− was less than Lepr db/db ,ApoE −/− mice (7.3±1 vs 13.9±1.7, p=0.003) and not significantly greater than Lepr +/+ ,ApoE −/− mice (7.3±1 vs 4.3±0.9, p=0.06 ). Hepatic steatosis and adipose inflammation were also reduced in Lepr s/s ,ApoE −/− mice compared to Lepr db/db ,ApoE −/− mice. In a mouse model of obesity and hyperlipidemia, leptin receptor signaling confers protection against hepatic steatosis, fat inflammation, and atherosclerosis. These effects are independent of leptin effects on energy balance. This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).

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Leptin receptor expression in the human erythroleukemia cell line K562

Aktuelle Ernährungsmedizin ◽

10.1055/s-2003-816373 ◽

2003 ◽

Vol 28 (05) ◽

Author(s):

C Peiser ◽

K Hupe-Sodmann ◽

RE Lang

Keyword(s):

Cell Line ◽

Leptin Receptor ◽

Receptor Expression ◽

Erythroleukemia Cell

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An Allosteric Glucagon Receptor Antagonist, LGD-6972, Displays Biased Receptor Signaling

Diabetes ◽

10.2337/db18-1117-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1117-P ◽

Cited By ~ 2

Author(s):

ERIC G. VAJDA ◽

LIN ZHI ◽

KEITH MARSCHKE

Keyword(s):

Receptor Antagonist ◽

Receptor Signaling ◽

Glucagon Receptor ◽

Glucagon Receptor Antagonist

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Faculty Opinions recommendation of Disruption of leptin receptor expression in the pancreas directly affects beta cell growth and function in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1092151.553044 ◽

2007 ◽

Author(s):

Raghavendra Mirmira

Keyword(s):

Cell Growth ◽

Beta Cell ◽

Leptin Receptor ◽

Receptor Expression ◽

Beta Cell Growth ◽

And Function

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The Neuronal Actions of Leptin and the Implications for Treating Alzheimer’s Disease

Pharmaceuticals ◽

10.3390/ph14010052 ◽

2021 ◽

Vol 14 (1) ◽

pp. 52

Author(s):

Kirsty Hamilton ◽

Jenni Harvey

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Hippocampal Formation ◽

Synaptic Function ◽

Receptor Expression ◽

Neuroprotective Actions ◽

Novel Target ◽

Leptin System

It is widely accepted that the endocrine hormone leptin controls food intake and energy homeostasis via activation of leptin receptors expressed on hypothalamic arcuate neurons. The hippocampal formation also displays raised levels of leptin receptor expression and accumulating evidence indicates that leptin has a significant impact on hippocampal synaptic function. Thus, cellular and behavioural studies support a cognitive enhancing role for leptin as excitatory synaptic transmission, synaptic plasticity and glutamate receptor trafficking at hippocampal Schaffer collateral (SC)-CA1 synapses are regulated by leptin, and treatment with leptin enhances performance in hippocampus-dependent memory tasks. Recent studies indicate that hippocampal temporoammonic (TA)-CA1 synapses are also a key target for leptin. The ability of leptin to regulate TA-CA1 synapses has important functional consequences as TA-CA1 synapses are implicated in spatial and episodic memory processes. Moreover, degeneration is initiated in the TA pathway at very early stages of Alzheimer’s disease, and recent clinical evidence has revealed links between plasma leptin levels and the incidence of Alzheimer’s disease (AD). Additionally, accumulating evidence indicates that leptin has neuroprotective actions in various AD models, whereas dysfunctions in the leptin system accelerate AD pathogenesis. Here, we review the data implicating the leptin system as a potential novel target for AD, and the evidence that boosting the hippocampal actions of leptin may be beneficial.

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SAT-604 The Role of the Focal Adhesion Kinase Family in Leptin Receptor Signaling

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.666 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Colleen Hadley ◽

Isin Cakir ◽

Roger D Cone

Keyword(s):

Food Intake ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Leptin Receptor ◽

Kinase Activity ◽

Cytokine Receptor ◽

Receptor Signaling ◽

Kinase Family ◽

Stat3 Phosphorylation

Abstract Overweight and obesity are global concerns affecting nearly one third of the world population. These conditions are characterized by increased adiposity and are accompanied by a proportional increase in circulating leptin, an anorexigenic adipokine. Leptin is responsible for signaling peripheral energy status to the central nervous system to modulate food intake and energy expenditure. As such, neurons within the hypothalamus expressing the long isoform of leptin receptor (LepRb), a type I cytokine receptor, are primarily responsible for mediating the effects of leptin, which signal predominantly through the JAK2-STAT3 transduction mechanism. STAT3 is a latent transcription factor activated upon phosphorylation, which triggers its homodimerization and nuclear translocation. Evidence, however, for JAK2-independent, STAT3-dependent leptin receptor signaling mechanisms exist. FAK (focal adhesion kinase, Ptk2) and Pyk2 (protein tyrosine kinase 2b, Ptk2b) are a subset of nonreceptor protein tyrosine kinases and comprise the focal adhesion kinase family. FAK and Pyk2 are implicated in the regulation of cytokine receptor signaling. Furthermore, Pyk2 knockout mice have an obesity prone phenotype. Here, we studied the role of the focal adhesion kinases in leptin receptor signaling using genetic and pharmacological approaches. We found that overexpression of Pyk2 or FAK increased STAT3 phosphorylation (activation). Overexpression of a FAK or Pyk2 construct with impaired kinase activity, however, attenuated STAT3 phosphorylation, suggesting the increase in STAT3 phosphorylation is largely dependent upon kinase activity of FAK/Pyk2. Treatment of cells with a small molecule dual inhibitor of FAK and Pyk2 (PF431396) attenuated leptin-induced STAT3 phosphorylation in a mouse hypothalamic cell line. Importantly, this effect is independent of JAK2, as PF treatment of two independent JAK2-deficient cell lines exhibited similar attenuation of leptin-induced STAT3 phosphorylation. To assess the physiological relevance of FAK/Pyk2 in leptin receptor signaling in vivo, we administered PF compound to the lateral ventricle of 24-hour fasted lean wild-type mice followed by peripheral leptin administration. Intracerebroventricular (ICV) administration of PF suppressed the anorectic effect of leptin as evidenced by impaired inhibition of food intake upon refeeding. Accordingly, analysis of total hypothalamic lysates from these mice showed ICV PF impaired leptin-induced STAT3 phosphorylation. Taken together, these data suggest that Pyk2 and/or FAK play a role in leptin signal transduction.

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