Abstract
Insulin resistance is associated with aging in mice and humans. We have previously shown that administration of recombinant GDF11 (rGDF11) to aged mice alters aging phenotypes in the brain, skeletal muscle, and heart. While the closely related protein GDF8 has a role in metabolism, limited data are available on the potential metabolic effects of GDF11 or GDF8 in aging. To determine the metabolic effects of these two ligands, we administered rGDF11 or rGDF8 protein to young or aged mice fed a standard chow diet, short-term high-fat diet (HFD), or long-term HFD. Under nearly all of these diet conditions, administration of exogenous rGDF11 reduced body weight by 3–17% and significantly improved glucose tolerance in aged mice fed a chow (~30% vs. saline) or HF (~50% vs. saline) diet and young mice fed a HFD (~30%). On the other hand, exogenous rGDF8 showed signifcantly lesser effect or no effect at all on glucose tolerance compared to rGDF11, consistent with data demonstrating that GFD11 is a more potent signaling ligand than GDF8. Collectively, our results show that administration of exogenous rGDF11, but not rGDF8, can reduce diet-induced weight gain and improve metabolic homeostasis.
Highlights
Insulin resistance is associated with aging in mice and humans
We performed a head-to-head comparison between the phenotypic response observed after delivery of recombinant GDF11 (rGDF11) or delivery of recombinant GDF8 (rGDF8) in order to determine if a ligand-specific phenotypic outcome occurs
We found that daily injection of rGDF11 or rGDF8 at equal doses prevented weight gain in wild-type C57BL/6 young male mice (8-week-old; Fig. 1B and Fig. S1), and caused a significant reduction in body weight in aged mice (24-month-old; Fig. 1C and Fig. S1), compared to saline controls
Summary
Insulin resistance is associated with aging in mice and humans. We have previously shown that administration of recombinant GDF11 (rGDF11) to aged mice alters aging phenotypes in the brain, skeletal muscle, and heart. Under most of these diet conditions, administration of exogenous rGDF11 reduced body weight by 3–17% and significantly improved glucose tolerance in aged mice fed a chow (~30% vs saline) or HF (~50% vs saline) diet and young mice fed a HFD (~30%). Exogenous rGDF8 showed signifcantly lesser effect or no effect at all on glucose tolerance compared to rGDF11, consistent with data demonstrating that GFD11 is a more potent signaling ligand than GDF8. Aging is typically associated with impaired glucose tolerance, insulin resistance, and hepatosteatosis in both mice and humans These metabolic disorders correlate with increased adiposity[1], as well as an age-related decline in functional pancreatic β-cell mass (reviewed in[2]). Despite similarities in the sequence identity and signaling components engaged by these two ligands, our structural and in vitro functional analysis comparing GDF11 and GDF8 indicates that GDF11 is ~10-fold more potent than GDF825, a finding that supports the idea that GDF11 and GDF8 may serve more distinct roles than previously thought
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