Systemic GDF11 stimulates the secretion of adiponectin and induces a calorie restriction‐like phenotype in aged mice

Abstract

Aging is a negative regulator of general homeostasis, tissue function, and regeneration. Changes in organismal energy levels and physiology, through systemic manipulations such as calorie restriction and young blood infusion, can regenerate tissue activity and increase lifespan in aged mice. However, whether these two systemic manipulations could be linked has never been investigated. Here, we report that systemic GDF11 triggers a calorie restriction-like phenotype without affecting appetite or GDF15 levels in the blood, restores the insulin/IGF-1 signaling pathway, and stimulates adiponectin secretion from white adipose tissue by direct action on adipocytes, while repairing neurogenesis in the aged brain. These findings suggest that GDF11 has a pleiotropic effect on an organismal level and that it could be a linking mechanism of rejuvenation between heterochronic parabiosis and calorie restriction. As such, GDF11 could be considered as an important therapeutic candidate for age-related neurodegenerative and metabolic disorders. K E Y W O R D Sadiponectin, aging, calorie restriction, GDF11, heterochronic parabiosis, rejuvenation | 9 of 11 KATSIMPARDI eT Al. GDF11 (Peprotech, was dissolved in water, further diluted according to the manufacturer's instructions, and injected at a concentration of 1 mg/kg. Control mice (young or aged) were injected with equivalent volumes of saline. Injection concentration was chosen based on a pilot study with three different concentrations (0.1, 0.5, and 1.0 mg/kg) where consistent weight loss and brain rejuvenation were observed upon 1 mg/kg GDF11 administration. The half-life of GDF11 at these concentrations was found to be of 12 hr. | GDF11 administration

Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice

“…We tested the plasma of young and aged mice following the conclusion of the daily 0.5 mg/kg ligand dosing regimen, and we did not find any differences in circulating levels of GDF15 among the groups. This finding is consistent with another recent report showing that exogenous rGDF11 leads to a significant body weight reduction, independent of GDF15 levels, and no change in physical activity 10 . In contrast, the authors of that study did not observe a reduction in food intake, although they did not begin measuring food consumption until 3 days after the first injection 10 , the approximate time-frame when we observed a modest decrease in food intake.…”

“…In particular, rGDF11 treatment prevented weight gain and preserved lean mass in aged mice on a HFD, which is consistent with reductions in body weight observed in other studies following supplementation of GDF11 4,6,10 . Young and aged mice injected with rGDF11 displayed improved glucose tolerance compared to saline-injected control mice.…”

“…In contrast, the authors of that study did not observe a reduction in food intake, although they did not begin measuring food consumption until 3 days after the first injection 10 , the approximate time-frame when we observed a modest decrease in food intake. Those authors also observed that mice injected with rGDF11 had reduced WAT and increased serum adiponectin suggesting that rGDF11 may act to reduce body weight and WAT by stimulating adiponectin secretion 10 . Taken together, it is unlikely that the phenotypes invoked by rGDF11 are governed by a single mechanism but rather, that there are multiple mechanisms across many tissues and cell types responsible for the observed phenotypes.…”

Cardio- and Neurometabolic Adipobiology: Consequences and Implications for Therapy

“…Recently, research efforts presented GDF11 as an important circulating MTF that significantly ameliorates high-fat diet-induced obesity, hyperglycemia, insulin resistance and liver steatosis by reducing body weight and improving glucose homeostasis [ 68 , 69 ]. Moreover, GDF11 was reported to trigger a calorie restriction-like phenotype by stimulating adiponectin secretion from WAT by direct action on adipocytes [ 70 ].…”

Growth differentiation factor 11: a “rejuvenation factor” involved in regulation of age-related diseases?

“…Notably, GDF11 also comprises a circulating factor in blood [ 41 ]. However, there is inconsistency in the literature regarding circulating concentrations of GDF11 with age: reduction [ 42 , 43 ], elevation [ 19 ] or tendency for elevation [ 44 ], or no change [ 42 ].…”