Central Sfrp5 regulates hepatic glucose flux and VLDL-triglyceride secretion.

Abstract

OBJECTIVE:

Secreted frizzled-related protein 5 (Sfrp5) has been shown to be associated with energy homeostasis and insulin resistance in mouse models of obesity and diabetes. However, its central role in glucose and lipid metabolism is unknown.

METHODS:

HFD-fed rats received ICV infusions of vehicle or Sfrp5 during a pancreatic euglycemic clamp procedure. To delineate the pathway(s) by which ICV Sfrp5 modulates HGP and VLDL-TG secretion, we inhibited the hypothalamic KATP channel using glibenclamide, the DVC NMDA receptor with MK801, and selectively transected the hepatic branch of the vagal nerve while centrally infusing Sfrp5.

RESULTS:

ICV Sfrp5 in HFD-fed rats significantly increased the glucose infusion required to maintain euglycemia due to HGP inhibition during the clamp procedure; moreover, hepatic PEPCK and G6Pase expression was decreased, and InsR and Akt phosphorylation was increased in the liver. ICV Sfrp5 also decreased circulating triglyceride levels via inhibiting hepatic VLDL-TG secretion. These changes were accompanied by the inhibition of enzymes related to lipogenesis in the liver. ICV Sfrp5 significantly increased insulin-stimulated phosphorylation of InsR and Akt in the hypothalamus of HFD-fed rats, and insulin-stimulated immunodetectable PIP3 levels were higher in Sfrp5 group than in control group both in vitro and vivo. The glucose- and lipid-lowering effects of ICV Sfrp5 were eliminated by NMDA receptor or DVC KATP channel inhibition or HVAG.

CONCLUSIONS:

The present study demonstrates that central Sfrp5 signaling activates a previously unappreciated InsR-Akt-PI3k-KATP channel pathway in the hypothalamus and brain-hepatic vagus neurocircuitry to decrease HGP and VLDL-TG secretion.

• Authors: Yang Li, Mingyuan Tian, Mengliu Yang, Gangyi Yang, Jianrong Chen, Han Wang, Dongfang Liu, Hongyan Wang, Wuquan Deng, Zhiming Zhu, Hongting Zheng, Ling Li
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 103 Pg. 154029 (02 2020) ISSN: 1532-8600 [Electronic] United States
• PMID: 31770545 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Adipokines
• Lipoproteins, VLDL
• Sfrp5 protein, mouse
• Triglycerides
• secreted frizzled-related protein 5, rat
• very low density lipoprotein triglyceride
• Glucose

Topics

• Adaptor Proteins, Signal Transducing (physiology)
• Adipokines (physiology)
• Animals
• Carbohydrate Metabolism (genetics)
• Cells, Cultured
• Diabetes Mellitus, Experimental (genetics, metabolism, pathology)
• Glucose (metabolism)
• Hypothalamus (metabolism)
• Lipid Metabolism (genetics)
• Lipoproteins, VLDL (metabolism)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Rats
• Rats, Sprague-Dawley
• Secretory Pathway (genetics)
• Triglycerides (metabolism)
• Vagus Nerve (metabolism)