Pär Steneberg

Background: Circulating S-Klotho is increasingly recognized as an anti-aging protein linked to cardiovascular protection and metabolic regulation. Although exercise elevates S-Klotho, the dose–response threshold and metabolic determinants of this response in young adults with obesity, a population at heightened risk for cardiometabolic dysfunction, remain poorly characterized. To examine the acute effects of submaximal and maximal cycling on circulating S-Klotho in young adults with obesity and to identify key metabolic predictors of exercise-induced changes. Methods: Eighteen young (26 ± 3 years, BMI 30 ± 2 kg/m²) males and females completed incremental cycling to exhaustion. Serum S-Klotho was assessed at rest, after submaximal (SubMax), and post-maximal (Max) exercise. Covariates included cardiorespiratory fitness (VO_2max), iDXA body composition, HOMA-IR, and hsCRP. Predictor Screening and Partial Least Squares (PLS) regression with fivefold cross-validation were used to identify determinants of exercise-induced S-Klotho responses. Results: A significant acute increase in S-Klotho was observed (Main Effect of Time: F_(2,32) = 9.4, p = 0.0006). Post hoc analysis revealed an intensity-dependent threshold, with a significant surge occurring only between submaximal and maximal exertion (p = 0.021; Rest to Max: p = 0.0005). No significant sex differences or interactions were observed (p > 0.05). The PLS model explained 74% of the variance in S-Klotho changes, identifying systemic inflammation (Log₁₀[hsCRP]) and visceral adiposity as the primary predictive factors. Conclusions: Exhaustive exercise acutely increases circulating S-Klotho in young adults with obesity, independent of sex. This response is intensity-dependent and primarily driven by baseline metabolic risk factors. S-Klotho may represent an acute exercise-responsive biomarker linked to metabolic health in at-risk populations. These exploratory findings warrant confirmation in larger and adequately powered studies.

AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which — in diet-induced obese mice — increased glucose uptake in skeletal muscle, reduced β cell stress, and promoted β cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro- and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.