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

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. 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). Identifying signals that modulate adipose tissue mass, glucose tolerance, insulin sensitivity, and/or functional β-cell mass in aging mammals could provide new targets for treatment of metabolic syndrome and diabetes. We previously showed that rGDF11 administration to aging mice results in a broad range of beneficial effects on brain 3,4 , skeletal muscle 5 , and cardiac tissues 6,7. GDF11 is a circulating blood factor which belongs to the larger transforming growth factor β (TGFβ) superfamily of extracellular ligands. New data published from multiple labs indicate that exogenous delivery of rGDF11 to rodent models of hyperglycemia (e.g. fed a high-fat diet HFD) reduced fasting blood glucose levels and improved glucose tolerance. The mechanism(s) behind these metabolic improvements may be due to a significant, yet transient, reduction in body mass 8-10. In fact, recent data suggests that rGDF11 stimulates secretion of adiponectin and a caloric restriction-like phenotype 10. On the other hand, others have shown that higher dosages of exogenous rGDF11 or viral overexpression of GDF11 via plasmid or viral vector caused cachexia, premature death, and anorexia 11-15. It is possible that these conflicting reports are due to drastically different doses and/or methodology used to artifically raise circulating GDF11 levels. Similarly, opposing results have also been reported regarding how GDF8, also known as myostatin, effects energy balance and metabolism 16-21. GDF8 is classically described as a potent negative regulator of skeletal muscle mass in addition to playin...

Once a week consumption of Western diet over twelve weeks promotes sustained insulin resistance and non-alcoholic fat liver disease in C57BL/6J mice

“…In the current work, we have mimicked "cheat meal" consumption by giving to mice a HFHS diet once a week, somehow comparing it to people that sporadically eat "junk food". It has been described that the punctual or short-term consumption of fat and/or sugar enriched diets impairs glucose utilization [18,20,21,[41][42][43][44]. Our data here show that consumption of HFHS diet for 24 hours impairs glucose tolerance tests in mice.…”

Functional replacement of myostatin with GDF-11 in the germline of mice

“…Physiologically, Mstn Gdf11/Gdf11 mice appear to be relatively normal with respect to glucose metabolism despite having circulating GDF-11 levels that are increased ~ 30–40-fold. Based on the report that purified GDF-11 but not MSTN can improve glucose tolerance [ 57 ], one might have expected Mstn Gdf11/Gdf11 mice to have improved responses to glucose challenges compared to wild-type mice, but we observed no significant differences between Mstn Gdf11/Gdf11 and wild-type mice in glucose tolerance tests on either standard or high-fat diets. We did observe trends toward lower glucose values in glucose tolerance tests in mice maintained on high-fat diets, but these differences were not statistically significant, and in fact, Mstn Gdf11/Gdf11 female mice actually had slightly elevated fasting glucose levels that were statistically significant.…”

“…In particular, Mstn −/− mice are able to maintain normal or lower blood glucose levels despite having lower insulin levels [ 24 , 63 ]. In addition, GDF-11 is known to play an important role in pancreatic development [ 30 , 31 ], and administration of GDF-11, but not MSTN, protein to mice has been shown to improve glucose tolerance [ 57 ]. As shown in Table 1 , fasting blood glucose levels were slightly higher in Mstn Gdf11/Gdf11 females compared to Mstn +/+ controls maintained on standard diets, but no statistically significant differences were seen in male mice on standard diets or in either males or females maintained on high-fat diets for 8 weeks.…”

“…Genetic studies have suggested that MSTN has both autocrine/paracrine and endocrine modes of action [ 54 ], although very little is known about the functions of GDF-11 and its mode of action in adult animals. Although overexpression of either MSTN [ 22 ] or GDF-11 [ 55 , 56 ] has been shown to induce a cachexia-like syndrome in adult mice, at least one study has reported distinct effects of giving MSTN and GDF-11 protein exogenously to mice, suggesting that these two molecules may have inherent differences in their biological properties [ 57 ]. Here, we addressed the functional equivalence of these two molecules by replacing the portion of the Mstn gene encoding its mature domain with the corresponding portion of Gdf11 in the germline of mice.…”

Growth differentiation factor 11 attenuates cardiac ischemia reperfusion injury via enhancing mitochondrial biogenesis and telomerase activity

“…Intriguingly, accumulating evidence suggests that GDF11 is cardioprotective in various pathological states. Deletion of GDF11 in cardiomyocytes leads to left ventricular dilation [ 9 ], while exogenous recombinant GDF11 can alleviate diet-induced weight gain and improve metabolic homeostasis [ 10 ]. Although GDF11 has been suggested to have an antihypertrophic effect in aging mice and patients [ 6 , 11 ], the effects of endogenous GDF11 on myocardial ischemia or ischemia/reperfusion (IR) as well as its underlying mechanisms have not been systematically investigated.…”