Selective inhibition of intestinal 5-HT improves neurobehavioral abnormalities caused by high-fat diet mice

Apr 2, 2019Metabolic brain disease

Blocking gut serotonin improves brain and behavior problems in mice on a high-fat diet

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Abstract

At the 4th week of high-fat diet feeding, significant improvements in glucose tolerance and neurobehavioral performance were observed with specific pharmacologic treatments.

High-fat diet feeding in mice was associated with increased total cholesterol and triglyceride levels.
The pharmacologic inhibitor of gut-derived serotonin, LP533401, and simvastatin improved impaired glucose tolerance, while benzafibrate did not show significant effects.
LP533401, simvastatin, and benzafibrate alleviated depression-like behaviors in various neurobehavioral tests.
LP533401 and simvastatin reversed changes in gene expression related to serotonin synthesis in the brains of high-fat diet-treated mice, but benzafibrate did not.
Treatment with LP533401, simvastatin, and benzafibrate restored the reduced expression of serotonin receptors in the hippocampus of high-fat diet mice.

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Recent literature reported the adverse effects of high-fat diet (HFD) on animal's emotional and cognitive function. An HFD-induced obesity/hyperlipidemia is accompanied by hormonal and neurochemical changes that can lead to depression. The important roles of gut-derived serotonin (5-Hydroxytryptamine, 5-HT) during this processing have been increasingly focused. Hence, to determine the potential role of gut-derived serotonin, HFD model was established in C57BL/6 mice. At the 4th week of feeding, a pharmacologic inhibitor of gut-derived 5-HT synthesis LP533401 (12.5 mg/kg/day), simvastatin (SIM) (5 mg/kg/day) and benzafibrate (BZ) (75 mg/kg/day) were administered for two weeks by oral gavage. Then, intraperitoneal glucose tolerance test (IPGTT), open field test (OFT), tail suspension test (TST), forced swim test (FST), sucrose preference test (SPT) were used to evaluate metabolic and neurobehavioral performances. Immunohistochemical staining, real-time quantitative PCR and other methods were to explore possible mechanisms. It was found that HFD feeding and drug treatments had some significant effects on neurobehaviors and brain: (1) All administrations reduced the total cholesterol (TC) and triglyceride (TG) parametric abnormality caused by HFD. LP533401 and SIM could significantly improve the impaired glucose tolerance, while BZ had no significant effect. (2) LP533401, SIM and BZ alleviated depression-like behavior of HFD mice in OFT, TST, FST and SPT. (3) LP533401 and SIM reversed the inhibition of Tryptophan Hydroxylase 2, Tph2 gene expression and the activation of Indoleamine 2,3-dioxy-Genase, IDO expression in HFD-treated brain, whereas BZ did not. (4) LP533401, SIM and BZ restored the inhibitory expression of 5-HTreceptor in HFD hippocampus. Conclusions: Selective inhibition of intestinal 5-HT can attenuate depressive-like behavior, reduce 5-HTR impairment in hippocampus and correct abnormal 5-HT pathway in brain while ameliorating HFD-induced glucose intolerance. Further experiments are warranted to define the adequate strategy of targeting peripheral 5-HT for the treatment of such co-morbidity. 1A1A

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Selective inhibition of intestinal 5-HT improves neurobehavioral abnormalities caused by high-fat diet mice

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