Abstract
The aging process and age‐related diseases all involve perturbed energy adaption and impaired ability to cope with adversity. Brain‐derived neurotrophic factor (BDNF) in the hypothalamus plays important role in regulation of energy balance. Our previous studies show that recombinant adeno‐associated virus (AAV)‐mediated hypothalamic BDNF gene transfer alleviates obesity, diabetes, and metabolic syndromes in both diet‐induced and genetic models. Here we examined the efficacy and safety of a built‐in autoregulatory system to control transgene BDNF expression mimicking the body's natural feedback systems in middle‐aged mice. Twelve‐month‐old mice were treated with either autoregulatory BDNF vector or yellow fluorescence protein (YFP) control, maintained on normal diet, and monitored for 28 weeks. BDNF gene transfer prevented the development of aging‐associated metabolic declines characterized by: preventing aging‐associated weight gain, reducing adiposity, reversing the decline of brown fat activity, increasing adiponectin while reducing leptin and insulin in circulation, improving glucose tolerance, increasing energy expenditure, alleviating hepatic steatosis, and suppressing inflammatory genes in the hypothalamus and adipose tissues. Moreover, BDNF treatment reduced anxiety‐like and depression‐like behaviors. These safety and efficacy data provide evidence that hypothalamic BDNF is a target for promoting healthy aging.
Highlights
The natural aging process and many age‐related diseases are associated with impaired metabolic adaption and declined ability to cope with stress
The gene expression signatures induced by hypothalamic Brain‐derived neurotrophic factor (BDNF) gene transfer were similar between iWAT (Figure 5d) and gWAT adipocytes (Figure 5e), including upregulation of Adrb3, Adipoq, glucose transporter type 4 (Glut4), insulin receptor (Insr), Hsl, Srebp1c and Pparg
Lipid extraction and quantification revealed that hepatic triglyceride levels were reduced by approximately 80% in BDNF mice compared to yellow fluorescence protein (YFP) mice (Figure 6b)
Summary
The natural aging process and many age‐related diseases are associated with impaired metabolic adaption and declined ability to cope with stress. BDNF signaling in the brain is thought to mediate at least some of the anti‐aging effects of an intermittent fasting regiment (Duan et al, 2003; Lee, Duan, & Mattson, 2002) data on the hypothalamus are not reported It is unclear how BDNF signaling in neurons is transferred to the periphery to improve the healthspan of many different organ systems. Our characterization of the HSA axis and the critical role of BDNF in this brain‐fat axis suggest a mechanism whereby hypothalamic BDNF, highly responsive to environmental stimuli, controls the HSA axis activity and thereby influences body composition, metabolism, immune function, and cancer via its preferential regulation of the phenotype and functions of adipose tissue. This dual‐cassette vector mimics the body’s natural feedback system to achieve autoregulation of the transgene and its efficacy has been examined in genetic models of obesity and diabetes such as db/db mice (Cao et al, 2009) and melanocortin‐4 receptor (MC4R) deficient mice (Siu et al, 2017)
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