Elsevier

Metabolism

Volume 103, February 2020, 154029
Metabolism

Basic Science
Central Sfrp5 regulates hepatic glucose flux and VLDL-triglyceride secretion

https://doi.org/10.1016/j.metabol.2019.154029Get rights and content
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Highlights

  • Secreted frizzled-related protein 5 protein level is down-regulated in the hypothalamus of obese animal models.

  • ICV sfrp5 in HFD-fed rats can reduce food intake and increase energy expenditure through activating neurons of the hypothalamic MBH.

  • ICV Sfrp5 improves N-methyl-d-aspartate(NMDA)receptor-mediated transmission of dorsal vagal complex (DVC) to enhance hepatic glucose metabolism and decrease VLDL-TG secretion by the hepatic vagus.

  • Central Sfrp5 potentiates insulin sensitivity of hypothalamic MBH via an insulin receptor-PI3K-Akt dependent pathway.

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.

Abbreviations

KATP
ATP-sensitive potassium channel
ICV
intracerebroventricular
HFD
high-fat-diet
HGP
hepatic glucose production
VLDL-TG
very low-density lipoproteins triglyceride
DVC
dorsal vagal complex
NMDA
N-methyl-d-aspartate
PEPCK
phosphoenolpyruatecarboxykinase
G6Pase
glucose-6- phosphatase
InsR
insulin receptor
Akt
Akt kinase
PIP3
phosphatidylinositol 3, 4, 5-trisphosphate
HVAG
hepatic branch vagotomy

Keywords

Sfrp5
Insulin resistance
VLDL-TG
Triglyceride

Cited by (0)

1

These authors contributed equally to this work.