Abstract |
Neuregulins (NRGs) are emerging as an important family of signaling ligands that regulate glucose and lipid homeostasis. NRG1 lowers blood glucose levels in obese mice, whereas the brown fat-enriched secreted factor NRG4 protects mice from high-fat diet-induced insulin resistance and hepatic steatosis. However, the therapeutic potential of NRGs remains elusive, given the poor plasma half-life of the native ligands. Here, we engineered a fusion protein using human NRG1 and the Fc domain of human IgG1 (NRG1-Fc) that exhibited extended half-life in circulation and improved potency in receptor signaling. We evaluated its efficacy in improving metabolic parameters and dissected the mechanisms of action. NRG1-Fc treatment triggered potent AKT activation in the liver, lowered blood glucose, improved insulin sensitivity, and suppressed food intake in obese mice. NRG1-Fc acted as a potent secretagogue for the metabolic hormone FGF21; however, the latter was largely dispensable for its metabolic effects. NRG1-Fc directly targeted the hypothalamic POMC neurons to promote membrane depolarization and increase firing rate. Together, NRG1-Fc exhibits improved pharmacokinetic properties and exerts metabolic benefits through dual inhibition of hepatic gluconeogenesis and caloric intake.
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Authors | Peng Zhang, Henry Kuang, Yanlin He, Sharon O Idiga, Siming Li, Zhimin Chen, Zhao Yang, Xing Cai, Kezhong Zhang, Matthew J Potthoff, Yong Xu, Jiandie D Lin |
Journal | JCI insight
(JCI Insight)
Vol. 3
Issue 5
(03 08 2018)
ISSN: 2379-3708 [Electronic] United States |
PMID | 29515030
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Immunoglobulin Fc Fragments
- Immunoglobulin G
- NRG1 protein, human
- Neuregulin-1
- Recombinant Fusion Proteins
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Topics |
- Animals
- Diet, High-Fat
(adverse effects)
- Disease Models, Animal
- Energy Intake
(drug effects)
- Fatty Liver
(drug therapy, etiology, metabolism)
- Gluconeogenesis
(drug effects)
- Half-Life
- Humans
- Immunoglobulin Fc Fragments
(administration & dosage, genetics)
- Immunoglobulin G
(administration & dosage, genetics)
- Liver
(drug effects, metabolism)
- Male
- Mice
- Neuregulin-1
(administration & dosage, genetics, pharmacokinetics)
- Obesity
(drug therapy, etiology, metabolism)
- Recombinant Fusion Proteins
(administration & dosage, genetics, pharmacokinetics)
- Treatment Outcome
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