Fatty acid type-specific regulation of SIRT1 does not affect insulin sensitivity in human skeletal muscle.

The nicotinamide adenine dinucleotide-dependent deacetylase, sirtuin (SIRT)1, in skeletal muscle is reduced in insulin-resistant states. However, whether this is an initial mechanism responsible for mediating insulin resistance in human skeletal muscle remains to be investigated. Also, SIRT1 acts as a mitochondrial gene transcriptional regulator and is induced by a short-term, high-fat diet (HFD) in human skeletal muscle. Whether saturated or unsaturated fatty acids (FAs) in the diet are important for this is unknown. We subjected 17 healthy, young men to a eucaloric control (Con) diet and 1 of 2 hypercaloric [+75% energy (E%)] HFDs for 3 d enriched in either saturated (Sat) FA (79 E% fat; Sat) or unsaturated FA (78 E% fat; Unsat). After Sat, SIRT1 protein content and activity in skeletal muscle increased ( P < 0.05; ∼40%) while remaining unchanged after Unsat. Whole-body insulin sensitivity and insulin-stimulated leg glucose uptake were reduced ( P < 0.01; ∼20%) to a similar extent compared to Con after both HFDs. We demonstrate a novel FA type-dependent regulation of SIRT1 protein in human skeletal muscle. Moreover, regulation of SIRT1 does not seem to be an initiating factor responsible for mediating insulin resistance in human skeletal muscle.-Fritzen, A. M., Lundsgaard, A.-M., Jeppesen, J. F., Sjøberg, K. A., Høeg, L. D., Deleuran, H. H., Wojtaszewski, J. F. P., Richter, E. A., Kiens, B. Fatty acid type-specific regulation of SIRT1 does not affect insulin sensitivity in human skeletal muscle.

Preclinical evaluation of a protracted GLP-1/glucagon receptor co-agonist: Translational difficulties and pitfalls.

During recent years combining GLP-1 and glucagon receptor agonism with the purpose of achieving superior weight loss and metabolic control compared to GLP-1 alone has received much attention. The superior efficacy has been shown by several in preclinical models but has been difficult to reproduce in humans. In this paper, we present the pre-clinical evaluation of NN1177, a long-acting GLP-1/glucagon receptor co-agonist previously tested in clinical trials. To further investigate the contribution from the respective receptors, two other co-agonists (NN1151, NN1359) with different GLP-1-to-glucagon receptor ratios were evaluated in parallel. In the process of characterizing NN1177, species differences and pitfalls in traditional pre-clinical evaluation methods were identified, highlighting the translational challenges in predicting the optimal receptor balance in humans. In diet-induced obese (DIO) mice, NN1177 induced a dose-dependent body weight loss, primarily due to loss of fat mass, and improvement in glucose tolerance. In DIO rats, NN1177 induced a comparable total body weight reduction, which was in contrast mainly caused by loss of lean mass, and glucose tolerance was impaired. Furthermore, despite long half-lives of the three co-agonists, glucose control during steady state was seen to depend on compound exposure at time of evaluation. When evaluated at higher compound exposure, glucose tolerance was similarly improved for all three co-agonists, independent of receptor balance. However, at lower compound exposure, glucose tolerance was gradually impaired with higher glucagon receptor preference. In addition, glucose tolerance was found to depend on study duration where the effect of glucagon on glucose control became more evident with time. To conclude, the pharmacodynamic effects at a given GLP-1-to-glucagon ratio differs between species, depends on compound exposure and study length, complicating the identification of an optimally balanced clinical candidate. The present findings could partly explain the low number of clinical successes for this dual agonism.

Exercise increases circulating GDF15 in humans.

OBJECTIVE: The growth differentiation factor 15 (GDF15) is a stress-sensitive circulating factor that regulates systemic energy balance. Since exercise is a transient physiological stress that has pleiotropic effects on whole-body energy metabolism, we herein explored the effect of exercise on a) circulating GDF15 levels and b) GDF15 release from skeletal muscle in humans. METHODS: Seven healthy males either rested or exercised at 67% of their VO2max for 1 h and blood was sampled from the femoral artery and femoral vein before, during, and after exercise. Plasma GDF15 concentrations were determined in these samples. RESULTS: Plasma GDF15 levels increased 34% with exercise (p < 0.001) and further increased to 64% above resting values at 120 min (p < 0.001) after the cessation of exercise. There was no difference between the arterial and venous GDF15 concentration before, during, and after exercise. During a resting control trial, GDF15 levels measured in the same subjects were unaltered. CONCLUSIONS: Vigorous submaximal exercise increases circulating GDF15 levels in humans, but skeletal muscle tissue does not appear to be the source.

GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand.

Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-ß superfamily and is associated with body-weight regulation in humans and rodents. However, the cognate receptor of GDF15 is unknown. Here we show that GDF15 binds specifically to GDNF family receptor α-like (GFRAL) with high affinity, and that GFRAL requires association with the coreceptor RET to elicit intracellular signaling in response to GDF15 stimulation. We also found that GDF15-mediated reductions in food intake and body weight of mice with obesity were abolished in GFRAL-knockout mice. We further found that GFRAL expression was limited to hindbrain neurons and not present in peripheral tissues, which suggests that GDF15-GFRAL-mediated regulation of food intake is by a central mechanism. Lastly, given that GDF15 did not increase energy expenditure in treated mice with obesity, the anti-obesity actions of the cytokine are likely driven primarily by a reduction in food intake.