Journal article
NRG1-Fc improves metabolic health via dual hepatic and central action
JCI insight, Vol.3(5), e98522
03/08/2018
DOI: 10.1172/jci.insight.98522
PMCID: PMC5922292
PMID: 29515030
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.
NRG1-Fc fusion protein improves metabolic profile in obesity through dual inhibition of hepatic gluconeogenesis and food intake.
Details
- Title: Subtitle
- NRG1-Fc improves metabolic health via dual hepatic and central action
- Creators
- Peng Zhang - Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan, USAHenry Kuang - Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan, USAYanlin He - Children’s Nutrition Research Center, Department of Pediatrics and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USASharon O Idiga - Department of Pharmacology and Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USASiming Li - Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan, USAZhimin Chen - Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan, USAZhao Yang - Center for Molecular Medicine and Genetics, Department of Immunology and Biochemistry, Wayne State University School of Medicine, Detroit, Michigan, USAXing Cai - Children’s Nutrition Research Center, Department of Pediatrics and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USAKezhong Zhang - Center for Molecular Medicine and Genetics, Department of Immunology and Biochemistry, Wayne State University School of Medicine, Detroit, Michigan, USAMatthew J Potthoff - Department of Pharmacology and Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAYong Xu - Children’s Nutrition Research Center, Department of Pediatrics and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USAJiandie D Lin - Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan, USA
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.3(5), e98522
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/jci.insight.98522
- PMID
- 29515030
- PMCID
- PMC5922292
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- GM007863 / National Institutes of Health AG055379 / National Institutes of Health DK106104 / National Institutes of Health DK102456 / ; DK117281 / ;
- Language
- English
- Date published
- 03/08/2018
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984040265302771
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