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Published on: October 23, 2018
Hepatic Src homology phosphatase 2 regulates energy balance in mice
Naoto Nagata1, Kosuke Matsuo, Ahmed Bettaieb
1Department of Nutrition, University of California Davis, Davis, California 95616, USA.
Abstract:
The Src homology 2 domain-containing protein-tyrosine phosphatase Src homology phosphatase 2 (Shp2) is a negative regulator of hepatic insulin action in mice fed regular chow. To investigate the role of hepatic Shp2 in lipid metabolism and energy balance, we determined the metabolic effects of its deletion in mice challenged with a high-fat diet (HFD). We analyzed body mass, lipid metabolism, insulin sensitivity, and glucose tolerance in liver-specific Shp2-deficient mice (referred to herein as LSHKO) and control mice fed HFD. Hepatic Shp2 protein expression is regulated by nutritional status, increasing in mice fed HFD and decreasing during fasting. LSHKO mice gained less weight and exhibited increased energy expenditure compared with control mice. In addition, hepatic Shp2 deficiency led to decreased liver steatosis, enhanced insulin-induced suppression of hepatic glucose production, and impeded the development of insulin resistance after high-fat feeding. At the molecular level, LSHKO exhibited decreased hepatic endoplasmic reticulum stress and inflammation compared with control mice. In addition, tyrosine and serine phosphorylation of total and mitochondrial signal transducer and activator of transcription 3 were enhanced in LSHKO compared with control mice. In line with this observation and the increased energy expenditure of LSHKO, oxygen consumption rate was higher in liver mitochondria of LSHKO compared with controls. Collectively, these studies identify hepatic Shp2 as a novel regulator of systemic energy balance under conditions of high-fat feeding.
Insights
Deleting the protein tyrosine phosphatase Shp2 in the liver of mice fed a high-fat diet reduced weight gain and improved insulin sensitivity. This highlights Shp2
Area of Science:
- Metabolic research
- Molecular biology
- Endocrinology
Background:
- The protein tyrosine phosphatase Shp2 regulates hepatic insulin action.
- Hepatic Shp2 expression increases with high-fat diet (HFD) and decreases with fasting.
- Its role in lipid metabolism and energy balance under HFD is not fully understood.
Purpose of the Study:
- To investigate the metabolic effects of liver-specific Shp2 deletion (LSHKO) in mice fed a high-fat diet.
- To analyze the impact on lipid metabolism, energy balance, and insulin sensitivity.
- To elucidate the molecular mechanisms underlying these effects.
Main Methods:
- Generation of liver-specific Shp2-deficient (LSHKO) mice.
- Feeding LSHKO and control mice a high-fat diet (HFD).
- Analysis of body mass, lipid metabolism, glucose tolerance, insulin sensitivity, hepatic endoplasmic reticulum stress, inflammation, and mitochondrial respiration.
Main Results:
- LSHKO mice exhibited reduced weight gain and increased energy expenditure compared to controls on HFD.
- Hepatic Shp2 deficiency decreased liver steatosis, enhanced insulin suppression of glucose production, and prevented HFD-induced insulin resistance.
- LSHKO mice showed reduced hepatic ER stress and inflammation, with enhanced STAT3 phosphorylation and increased mitochondrial oxygen consumption.
Conclusions:
- Hepatic Shp2 is a novel regulator of systemic energy balance during high-fat feeding.
- Deletion of hepatic Shp2 improves metabolic parameters and insulin sensitivity under HFD conditions.
- Targeting hepatic Shp2 may offer a therapeutic strategy for metabolic disorders associated with obesity and insulin resistance.
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