Aging-Induced Brain-Derived Neurotrophic Factor in Adipocyte Progenitors Contributes to Adipose Tissue Dysfunction

Abstract

Aging-related adipose tissue dysfunction contributes to the progression of chronic metabolic diseases. We investigated the role of age-dependent expression of a neurotrophin, brain-derived neurotrophic factor (BDNF) in adipose tissue. Pro-BDNF expression was elevated in epididymal white adipose tissue (eWAT) with advanced age, which was associated with the reduction in sympathetic innervation. Interestingly, BDNF expression was enriched in PDGFR + adipocyte progenitors isolated from eWAT, with age-dependent increase in expression. In vitro pro-BDNF treatment caused apoptosis in adipocytes differentiated from C3H10T1/2 cells, and siRNA knockdown of sortilin mitigated these effects. Tamoxifen-inducible PDGFR + cell-specific deletion of BDNF (BDNF Pdgfra KO) reduced pro-BDNF expression in eWAT, prevented age-associated declines in sympathetic innervation and mitochondrial content in eWAT, and improved insulin sensitivity. Moreover, BDNF Pdgfra KO mice showed reduced expression of aging-induced inflammation and senescence markers in eWAT. Collectively, these results identified the upregulation of pro-BDNF expression in adipocyte progenitors as a feature of visceral white adipose tissue aging and suggested that inhibition of BDNF expression in adipocyte progenitors is potentially beneficial to prevent aging-related adipose tissue dysfunction.

COVID-19 Outcome Relates With Circulating BDNF, According to Patient Adiposity and Age

“…Interestingly, serum BDNF levels didn't differ across severity groups in patients >60yrs, while a reduction of BDNF in patients <60 yrs was observed with the progression of COVID-19 severity. This data reinforces the idea that increased mature BDNF isoform is related to the improvement of metabolic function, while the pro-BDNF isoform is related to the adipose tissue disfunction as observed by Song et al (42). In addition, higher cortisol levels found in obese subjects and a tendency (p = 0.06) for higher levels of the same hormone in patients who died (ICU-death) suggest central hyperstimulation on the hypothalamus-adrenal-pituitary axis during SARS-CoV-2 infection.…”

“…Different studies have shown either that circulating BDNF levels are higher in obese subjects than in controls (39,40) or that there are no differences between the two groups (41). An upregulation of pro-BDNF expression in PDGFRα + adipocyte progenitors was indicated as a feature of adipose tissue aging, suggesting that inhibition of BDNF expression in adipocyte progenitors could be potentially beneficial to prevent age-related adipose tissue dysfunction (42). However, in our study, we evaluated serum mature BDNF levels that have opposite effects of pro-BDNF (43).…”

Potential Biochemical Mechanisms of Brain Injury in Diabetes Mellitus

“…Thus, decreased NAA could be a potential biomarker of central neuronal dysfunction and may be useful in evaluating progression of neuropathy in DM [ 17 ]. Moreover, studies focusing on brain derived neurotrophic factor (BDNF), one of the most essential neurotrophic factors in the brain [ 27 ], and dipeptidyl peptidase-4 (DPP4), initially identified as a therapeutic target for type 2 diabetes [ 28 ], have demonstrated that both BDNF and DPP4 function as an antigenic enzyme involved in hyperglycemia, oxidative stress and inflammation-associated insulin resistance [ 29 ]). These studies provide evidence for the role of increased DPP4 and decreased BDNF in type 2-DM-related cognitive dysfunction [ 30 ], suggesting that DPP4 to BDNF ratio could be a novel biomarker for DM-related cognitive impairment [ 31 ].…”

Is Brain-Derived Neurotrophic Factor a Metabolic Hormone in Peripheral Tissues?

“…Recently, it was proposed that the BDNF production in progenitor cells of WAT is detrimental to the tissue’s metabolic health during aging. Using the inducible adipocyte progenitor-specific Bdnf knockout (BDNF Pdgfra KO) mice, Song et al demonstrated that abolishing the production of BDNF in adipocyte progenitor cells prevents the aging-induced inflammation and glucose intolerance [ 41 ]. Because in vitro assays showed that pro-BDNF promoted adipocyte apoptosis and reduced the cellular mitochondria content, the authors concluded that an excessive pro-BDNF production in the adipose progenitor cells of aged animals triggered the death of adipocytes, causing the infiltration of immune cells and deterioration of the metabolic fitness.…”