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Dietary Genistein Could Modulate Hypothalamic Circadian Entrainment, Reduce Body Weight, and Improve Glucose and Lipid Metabolism in Female Mice.

ABSTRACT: Genistein has beneficial effects on metabolic disorders. However, the specific mechanism is not clearly understood. In light of the significant role of the hypothalamus in energy and metabolic homeostasis, this study was designed to explore whether dietary genistein intake could mitigate the harmful effects of a high-fat diet on glucose and lipid metabolism and whether any alterations caused by dietary genistein were associated with hypothalamic gene expression profiles. C57BL/6 female mice were fed a high-fat diet without genistein (HF), a high-fat diet with genistein (HFG), or a normal control diet (CON) for 8 weeks. Body weight and energy intake were assessed. At the end of the study, glucose tolerance and serum levels of insulin and lipids were analyzed. Hypothalamic tissue was collected for whole transcriptome sequencing and reverse transcription quantitative PCR (RT-qPCR) validation. Energy intake and body weight were significantly reduced in the mice of the HFG group compared with those of the HF group. Mice fed the HFG diet had improved glucose tolerance and decreased serum triacylglycerol, free fatty acids, and low-density lipoprotein cholesterol compared with those fed the HF diet. The HFG diet also modulated gene expression in the hypothalamus; the most abundant genes were enriched in the circadian entrainment pathway. Dietary genistein intake could reduce body weight, improve glucose and lipid metabolism, and regulate hypothalamic circadian entrainment. The ability of genistein intake to influence regulation of the hypothalamic circadian rhythm is important since this could provide a novel target for the treatment of obesity and diabetes.

SUBMITTER: Zhou L

PROVIDER: S-EPMC6500629 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Project description:ObjectiveMetabolic Syndrome, which can be induced or exacerbated by current antipsychotic drugs (APDs), is highly prevalent in schizophrenia patients. Recent preclinical and clinical evidence suggest that agonists at trace amine-associated receptor 1 (TAAR1) have potential as a new treatment option for schizophrenia. Intriguingly, preclinical tudies have also identified TAAR1 as a novel regulator of metabolic control. Here we evaluated the effects of three TAAR1 agonists, including the clinical development candidate ulotaront, on body weight, metabolic parameters and modulation of neurocircuits implicated in homeostatic and hedonic feeding.MethodsEffects of TAAR1 agonists (ulotaront, RO5166017 and/or RO5263397) on body weight, food intake and/or metabolic parameters were investigated in rats fed a high-fat diet (HFD) and in a mouse model of diet-induced obesity (DIO). Body weight effects were also determined in a rat and mouse model of olanzapine-, and corticosterone-induced body weight gain, respectively. Glucose tolerance was assessed in lean and diabetic db/db mice and fasting plasma glucose and insulin examined in DIO mice. Effects on gastric emptying were evaluated in lean mice and rats. Drug-induced neurocircuit modulation was evaluated in mice using whole-brain imaging of c-fos protein expression.ResultsTAAR1 agonists improved oral glucose tolerance by inhibiting gastric emptying. Sub-chronic administration of ulotaront in rats fed a HFD produced a dose-dependent reduction in body weight, food intake and liver triglycerides compared to vehicle controls. In addition, a more rapid reversal of olanzapine-induced weight gain and food intake was observed in HFD rats switched to ulotaront or RO5263397 treatment compared to those switched to vehicle. Chronic ulotaront administration also reduced body weight and improved glycemic control in DIO mice, and normalized corticosterone-induced body weight gain in mice. TAAR1 activation increased neuronal activity in discrete homeostatic and hedonic feeding centers located in the dorsal vagal complex and hypothalamus with concurrent activation of several limbic structures.ConclusionThe current data demonstrate that TAAR1 agonists, as a class, not only lack APD-induced metabolic liabilities but can reduce body weight and improve glycemic control in rodent models. The underlying mechanisms likely include TAAR1-mediated peripheral effects on glucose homeostasis and gastric emptying as well as central regulation of energy balance and food intake.

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Dietary Genistein Could Modulate Hypothalamic Circadian Entrainment, Reduce Body Weight, and Improve Glucose and Lipid Metabolism in Female Mice.

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