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Context One acute bout of exercise leads to a rapid increase in the systemic cytokine concentration. Regular exercise might alter the cytokine response, in particular in beforehand untrained and obese individuals. Objective Using a proximity extension assay, we studied the effects of acute exercise as well as endurance training on a panel of 92 cytokines related to inflammation. Methods A total of 22 individuals (30 ± 9 years; peak oxygen uptake [VO2peak] 25.2 ± 4.2 mL/[kg × min]; body mass index [BMI] 31.7 ± 4.4) participated in an 8-week endurance exercise intervention. Blood samples were collected before and immediately after 30 minutes’ ergometer exercise at 80% VO2peak. Results Before and after the training intervention, 40 and 37 cytokines, respectively, were acutely increased more than 1.2-fold (Benjamini-Hochberg [BH]-adjusted P < .05). The exercise intervention did not change the acute increase in cytokines nor the resting cytokine levels, whereas fitness was improved and adiposity reduced. The increase in fitness led to a slight increase in power output when exercising at the same heart rate, which might explain the comparable increase in cytokines before and after the intervention. The largest acute increase was found for OSM, TGFA, CXCL1 and 5, and TNFSF14 (≥ 1.9-fold, BH-adjusted P < .001). The transcript levels of these proteins in whole blood were also elevated, particularly in the trained state. Only the acute increase in IL6 (1.3-fold) was related to the increase in lactate, confirming the lactate-driven secretion of IL6. Conclusion Our comprehensive proteomics approach detected several underexplored serum exerkines with up to now less understood function in the adaptation to exercise.

Physical exercise is a powerful measure to prevent cardiometabolic diseases. However, the individual response to lifestyle interventions is variable and cannot, to date, be predicted. N-Lactoylphenylalanine (Lac-Phe) produced during exercise has recently been shown to mediate weight loss in obese mice. Lac-Phe could also contribute to, and potentially explain differences in, the effectiveness of exercise interventions in humans. Sedentary overweight and obese subjects completed an 8-week supervised endurance exercise intervention (n = 22). Before and after the intervention, plasma levels of Lac-Phe were determined by UHPLC-MS in the resting state and immediately after an acute bout of endurance exercise. Adipose tissue volume was quantified using MRI. Acute exercise caused a pronounced increase in Lac-Phe, both before and after the intervention. Higher levels of Lac-Phe after acute exercise were associated with a greater reduction in abdominal subcutaneous and, to a lower degree, visceral adipose tissue during the intervention. Lac-Phe produced during physical activity could contribute to weight loss by acting as a signaling molecule that regulates food intake, as previously shown in mice. Quantification of Lac-Phe during an exercise test could be employed as a tool to predict and potentially improve the individual response to exercise-based lifestyle interventions in overweight humans and those with obesity.

ObjectiveThe exercise-inducible metabolite N-Lactoylphenylalanine (Lac-Phe) has recently been shown to reduce food intake and adipose tissue mass in mice. We addressed whether Lac-Phe could have a similar function in humans.MethodsSedentary subjects with overweight and obesity completed an 8-week supervised endurance exercise intervention (n=22). Before and after the intervention, blood plasma levels of Lac-Phe were determined by UHPLC-MS in the resting state and immediately after an acute endurance exercise test. Adipose tissue and muscle volume were quantified by MRI.ResultsAcute exercise caused a pronounced increase in Lac-Phe, both before and after the intervention. Higher levels of Lac-Phe after acute exercise were associated with a greater reduction in abdominal subcutaneous and, to a lower degree, visceral adipose tissue during the intervention.ConclusionsLac-Phe produced during physical activity could boost weight loss in humans with obesity and overweight, possibly by transmitting or enhancing the appetite-suppressing effects of lactate. Exercise-induced Lac-Phe could be employed to predict and, potentially, improve the effectiveness of lifestyle interventions in subjects with overweight and obesity.Trial RegistrationClinicaltrials.govNCT0315159022 May 2017https://clinicaltrials.gov/ct2/show/NCT03151590

Obesity, especially visceral fat accumulation, increases the risk of type 2 diabetes (T2D). The purpose of this study was to investigate the impact of T2D on the pancreatic fat depot. Pancreatic fat pads from 17 partial pancreatectomized patients (PPP) were collected, pancreatic preadipocytes isolated, and in vitro differentiated. Patients were grouped using HbA1c into normal glucose tolerant (NGT), prediabetic (PD), and T2D. Transcriptome profiles of preadipocytes and adipocytes were assessed by RNAseq. Insulin sensitivity was estimated by quantifying AKT phosphorylation on Western blots. Lipogenic capacity was assessed with oil red O staining, lipolytic activity via fatty acid release. Secreted factors were measured using ELISA. Comparative transcriptome analysis of preadipocytes and adipocytes indicates defective upregulation of genes governing adipogenesis ( NR1H3), lipogenesis ( FASN, SCD, ELOVL6, and FADS1), and lipolysis ( LIPE) during differentiation of cells from T2D–PPP. In addition, the ratio of leptin/adiponectin mRNA was higher in T2D than in NGT–PPP. Preadipocytes and adipocytes of NGT–PPP were more insulin sensitive than T2D–PPP cells in regard to AKT phosphorylation. Triglyceride accumulation was similar in NGT and T2D adipocytes. Despite a high expression of the receptors NPR1 and NPR2 in NGT and T2D adipocytes, lipolysis was stimulated by ANP 1.74-fold in NGT cells only. This stimulation was further increased by the PDE5 inhibitor dipyridamole (3.09-fold). Dipyridamole and forskolin increased lipolysis receptor independently 1.88-fold and 1.48-fold, respectively, solely in NGT cells. In conclusion, the metabolic status persistently affects differentiation and lipolysis of pancreatic adipocytes. These alterations could aggravate the development of T2D.

Context Exercise training improves glycemic control and increases mitochondrial content and respiration capacity in skeletal muscle. Rodent studies suggest that training increases mitochondrial respiration in adipose tissue. Objective To assess the effects of endurance training on respiratory capacities of human skeletal muscle and abdominal subcutaneous adipose tissue and to study the correlation with improvement in insulin sensitivity. Design Using high-resolution respirometry, we analyzed biopsies from 25 sedentary (VO2 peak 25.1 ± 4.0 VO2 mL/[kg*min]) subjects (16 female, 9 male; 29.8 ± 8.4 years) with obesity (body mass index [BMI] 31.5 ± 4.3 kg/m2), who did not have diabetes. They performed a supervised endurance training over 8 weeks (3 × 1 hour/week at 80% VO2 peak). Results Based on change in insulin sensitivity after intervention (using the Matsuda insulin sensitivity index [ISIMats]), subjects were grouped in subgroups as responders (>15% increase in ISIMats) and low-responders. The response in ISIMats was correlated to a reduction of subcutaneous and visceral adipose tissue volume. Both groups exhibited similar increases in fitness, respiratory capacity, and abundance of mitochondrial enzymes in skeletal muscle fibers. Respiratory capacities in subcutaneous adipose tissue were not altered by the intervention. Compared with muscle fibers, adipose tissue respiration showed a preference for β-oxidation and complex II substrates. Respiratory capacities were higher in adipose tissue from female participants. Conclusion Our data show that the improvement of peripheral insulin sensitivity after endurance training is not directly related to an increase in mitochondrial respiratory capacities in skeletal muscle and occurs without an increase in the respiratory capacity of subcutaneous adipose tissue.