Activation of Muscular TrkB by its Small Molecular Agonist 7,8-Dihydroxyflavone Sex-Dependently Regulates Energy Metabolism in Diet-Induced Obese Mice

Chan, Chi Bun; Tse, Margaret Chui Ling; Liu, Xia; Zhang, Shuai; Schmidt, Robin H.; Otten, Reed; Liu, Liegang; Ye, Keqiang

doi:10.1016/j.chembiol.2015.02.003

Cited by 66 publications

(68 citation statements)

References 52 publications

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“…Together, with other signaling analysis, the authors proposed that post-HI induced ER expression in female hippocampus couples the c-Src kinase to augment the TrkB phosphorylation, thereby reduces the cellular apoptosis and neuronal injury. In our recent study, we found that 7,8-DHF initiates the AMPK/CREB/uncoupling protein 1 (UCP1) pathway to increase the lipid oxidation and energy expenditure in muscle cells (Chan et al 2015). Concurred with these in vitro findings, administration of 7,8-DHF increased the energy expenditure of mice under high-fat diet (HFD) feeding, thus protecting these animals from gaining excess body weight.…”

Section: Sex-specific Functions Of Bdnfmentioning

confidence: 99%

Sex differences in brain‐derived neurotrophic factor signaling and functions

Chan

2016

J of Neuroscience Research

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148

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Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family that plays a critical role in numerous neuronal activities. Recent studies report that some functions or action mechanisms of BDNF vary in a sex-dependent manner. In particular, BDNF content in some brain parts and the tendency of developing BDNF-deficient-related diseases like depression is higher in female animals. With the support of other relevant studies, it is suggested that sex hormones or steroids can modulate the activities of BDNF, which may account for its functional discrepancy in different sexes. Indeed, the cross-talk between BDNF and sex steroids has been detected for decades and some sex steroids like estrogen have a positive regulatory effect to BDNF expression and signaling. Thus, the sex of animal models used is critical when studying the functions of BDNF in vivo. In this review, we will summarize our current findings on the difference in expression, signaling, and functions of BDNF between sexes. We will also discuss the potential mechanisms in mediating these differential responses with a specific emphasis on sex steroids. By presenting and discussing these findings, we encourage taking sex influences into consideration when designing experiments, interpreting results and drawing conclusions.

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Section: Sex-specific Functions Of Bdnfmentioning

confidence: 99%

Sex differences in brain‐derived neurotrophic factor signaling and functions

Chan

2016

J of Neuroscience Research

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148

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“…As a bioavailable chemical, 7,8-DHF can penetrate brain blood barrier upon intraperitoneal or oral administration to provoke TrkB and its downstream signaling, such as phosphoinositide 3-kinase/protein kinase B (Akt; Wu et al, 2014), to exert its central role in pathologic conditions. As a consequence of activating TrkB, 7,8-DHF inhibits obesity in female mice (Chan et al, 2015), reduces spine morphology abnormalities in fragile X syndrome (Tian et al, 2015), enhances axon regeneration and muscle renovation after peripheral nerves injuries (English et al, 2013), improves motor function and prolongs survival in Huntington’s disease (Jiang et al, 2013). Furthermore, it can reverse synapse loss and prevent memory deficits in Alzheimer’s disease (AD; Zhang et al, 2014a; Gao et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

7,8-Dihydroxyflavone Ameliorates Cognitive Impairment by Inhibiting Expression of Tau Pathology in ApoE-Knockout Mice

Tan

Nie

Zhu

et al. 2016

Front. Aging Neurosci.

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7,8-Dihydroxyflavone (7,8-DHF), a tyrosine kinase B agonist that mimics the neuroprotective properties of brain-derived neurotrophic factor, which can not efficiently deliver into the brain, has been reported to be useful in ameliorating cognitive impairment in many diseases. Researches have indicated that apolipoprotein E-knockout (ApoE-KO) mouse was associated with cognitive alteration via various mechanisms. Our present study investigated the possible mechanisms of cognitive impairment of ApoE-KO mouse fed with western type diet and the protective effects of 7,8-DHF in improving spatial learning and memory in ApoE-KO mouse. Five-weeks-old ApoE-KO mice and C57BL/6 mice were chronically treated with 7,8-DHF (with a dosage of 5 mg/kg) or vehicles orally for 25 weeks, and then subjected to Morris water maze at the age of 30 weeks to evaluate the cognitive performances. Afterward, histology analysis and western blotting were performed. Spatial learning and memory deficits were observed in ApoE-KO mice, which were consistent with higher expression of active-asparaginyl endopeptidase (active-AEP) as well as AEP-derived truncated tau N368 compared with normal group. In addition to that, long-term treatment of 7,8-DHF dramatically ameliorated cognitive decline in ApoE-KO mice, accompanied by the activation in phosphorylated protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway and down-regulated expression of tau S396 and PHF-tau (phosphorylated tau at ser396 and ser404 epitope). These findings suggested that cognitive impairment of ApoE-KO mouse might associate with tau pathology and 7,8-DHF could activate AKT and then phosphorylate its downstream molecule to inhibit expression of abnormal tau, meanwhile, 7,8-DHF could reduce the expression of active-AEP and then inhibit production of truncated tau N368.

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“…Conceivably, BDNF action in specific neuronal populations may have different, if not opposing effects on energy metabolism. Supporting this notion, the modulation of the BDNF pathway by TrkB agonists in vivo resulted in reduced, unchanged, or even increased food intake in rodents, depending on the pharmacological agent and the route of its administration . Also, peripheral administration of BDNF in non‐human primates led to a gain in appetite and increased adiposity .…”

Section: Discussionmentioning

confidence: 92%

SORCS 1 and SORCS 3 control energy balance and orexigenic peptide production

et al. 2018

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SORCS1 and SORCS3 are two related sorting receptors expressed in neurons of the arcuate nucleus of the hypothalamus. Using mouse models with individual or dual receptor deficiencies, we document a previously unknown function of these receptors in central control of metabolism. Specifically, SORCS1 and SORCS3 act as intracellular trafficking receptors for tropomyosin‐related kinase B to attenuate signaling by brain‐derived neurotrophic factor, a potent regulator of energy homeostasis. Loss of the joint action of SORCS1 and SORCS3 in mutant mice results in excessive production of the orexigenic neuropeptide agouti‐related peptide and in a state of chronic energy excess characterized by enhanced food intake, decreased locomotor activity, diminished usage of lipids as metabolic fuel, and increased adiposity, albeit at overall reduced body weight. Our findings highlight a novel concept in regulation of the melanocortin system and the role played by trafficking receptors SORCS1 and SORCS3 in this process.

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Activation of Muscular TrkB by its Small Molecular Agonist 7,8-Dihydroxyflavone Sex-Dependently Regulates Energy Metabolism in Diet-Induced Obese Mice

Cited by 66 publications

References 52 publications

Sex differences in brain‐derived neurotrophic factor signaling and functions

Sex differences in brain‐derived neurotrophic factor signaling and functions

7,8-Dihydroxyflavone Ameliorates Cognitive Impairment by Inhibiting Expression of Tau Pathology in ApoE-Knockout Mice

SORCS 1 and SORCS 3 control energy balance and orexigenic peptide production

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