Data from transgenic animal models suggest that exercise-induced autophagy is critical for adaptation to physical training, and that Unc-51 like kinase-1 (ULK1) serves as an important regulator of autophagy. Phosphorylation of ULK1 at Ser(555) stimulates autophagy, whereas phosphorylation at Ser(757) is inhibitory. To determine whether exercise regulates ULK1 phosphorylation in humans in vivo in a nutrient-dependent manner, we examined skeletal muscle biopsies from healthy humans after 1-h cycling exercise at 50% maximal O2 uptake on two occasions: 1) during a 36-h fast, and 2) during continuous glucose infusion at 0.2 kg/h. Physical exercise increased ULK1 phosphorylation at Ser(555) and decreased lipidation of light chain 3B. ULK1 phosphorylation at Ser(555) correlated positively with AMP-activated protein kinase-α Thr(172) phosphorylation and negatively with light chain 3B lipidation. ULK1 phosphorylation at Ser(757) was not affected by exercise. Fasting increased ULK1 and p62 protein expression, but did not affect exercise-induced ULK1 phosphorylation. These data demonstrate that autophagy signaling is activated in human skeletal muscle after 60 min of exercise, independently of nutritional status, and suggest that initiation of autophagy constitutes an important physiological response to exercise in humans.

Overt Cushing’s syndrome is a rare disorder with an annual incidence of 2–3/million of which benign adrenal adenomas account for 0.6/million. The female:male ratio is 3:1. Preliminary data indicate a high proportion of subclinical Cushing’s syndrome in certain risk populations such as patients with type 2 diabetes or osteoporosis. The clinical implications of these observations are presently unclear. Surgery remains first line treatment for overt disease and initial cure or remission is obtained in 65–85% of patients with Cushing’s disease. Late recurrences, however, occur in up to 20% and the risk does not seem to plateau even after 20 years of follow-up. A 2- to 3-fold increase in mortality is observed in most studies, and this excess mortality seems confined to patients in whom initial cure was not obtained. Cushing’s syndrome continues to pose diagnostic and therapeutic challenges and life-long follow-up is mandatory.

-Increased availability of lipids may conserve muscle protein during catabolic stress. Our study was designed to define 1) intracellular mechanisms leading to increased lipolysis and 2) whether this scenario is associated with decreased amino acid and urea fluxes, and decreased muscle amino acid release in obese subjects under basal and fasting conditions. We therefore studied nine lean and nine obese subjects twice, after 12 and 72 h of fasting, using measurements of mRNA and protein expression and phosphorylation of lipolytic and protein metabolic signaling molecules in fat and muscle together with whole body and forearm tracer techniques. Obese subjects displayed increased whole body lipolysis, decreased urea production rates, and decreased forearm muscle protein breakdown per 100 ml of forearm tissue, differences that persisted after 72 h of fasting. Lipolysis per fat mass unit was reduced in obese subjects and, correspondingly, adipose tissue hormone-sensitive lipase (HSL) phosphorylation and mRNA and protein levels of the adipose triglyceride lipase (ATGL) coactivator CGI58 were decreased. Fasting resulted in higher HSL phosphorylations and lower protein levels of the ATGL inhibitor G0S2. Muscle protein expressions of mammalian target of rapamycin (mTOR) and 4EBP1 were lower in obese subjects, and MuRf1 mRNA was higher with fasting in lean but not obese subjects. Phosphorylation and signaling of mTOR decreased with fasting in both groups, whereas ULK1 protein and mRNA levels increased. In summary, obese subjects exhibit increased lipolysis due to a large fat mass with blunted prolipolytic signaling, together with decreased urea and amino acid fluxes both in the basal and 72-h fasted state; this is compatible with preservation of muscle and whole body protein.obesity; fasting; protein breakdown; lipolysis; skeletal muscle; subcutaneous adipose tissue; human FASTING AND OBESITY ARE BOTH associated with increased levels of free fatty acids (FFAs) In the fasting state, FFA mobilization is promoted by the combined effects of reduced plasma insulin and increased levels of catecholamines, growth hormone, and cortisol (41) and, remarkably, decreased lipolytic effect of catecholamines in adipose tissue (AT) has consistently been demonstrated in obese subjects (12,31,32). In adipocytes, lipolysis is controlled by the sequential action of adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase that hydrolyze triglycerides to FFA and glycerol (25). It has previously been shown that ATGL protein levels increase and that the ATGL inhibitor G 0 /G 1 switch gene 2 (G0S2) protein and mRNA levels decrease during fasting in humans (26). A number of studies have shown that FFA and ketone bodies are decisive for protein conservation, in particular during fasting (6,22,27), but the underlying mechanisms remain elusive.The metabolic effects of fasting in obese subjects have been studied extensively, but the effects of obesity on amino acid metabolism remain unclear, and data from studies meas...

Competition between intermediates of glucose and fatty acids seems to play a causal role in insulin resistance induced by GH in human subjects.

Insulin resistance is a well-known physiological adaptation to prolonged fasting in healthy skeletal muscle. Obesity is associated with insulin resistance and metabolic inflexibility in skeletal muscle, and a pronounced increase in the risk of metabolic complications. Under the hypothesis that the metabolic traits of insulin resistance associated with prolonged fasting are different from insulin resistance associated with obesity, we examined nine obese and nine lean participants during 12 and 72h of fasting, respectively. Insulin resistance in obese participants was associated with impaired insulin signaling, and reduced levels of glucose-6-phosphate and TCA-cycle intermediates. 72h of fasting in lean participants reduced insulin-stimulated glucose uptake to levels similar to obese participants fasted for 12h. This was associated with increased lipid oxidation, but not accumulation of diacylglycerol or acylcarnitines and impairment of insulin signaling. Prolonged fasting was associated with pronounced increases in β-hydroxybutyrate and β- hydroxybutyrylcarnitine levels in skeletal muscle suggesting augmented ketone body metabolism. Fasting induced insulin resistance may be a consequence of substrate competition. The underlying mechanism behind insulin resistance in obesity is thus not comparable to the physiological adaptations in skeletal muscle induced by prolonged fasting in lean participants.

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A convincing amount of evidence has shown a beneficial effect of GLP-1 agonist treatment on cognitive function, memory and learning in experimental models of AD. GLP-1 analogues may therefore be the new therapeutic agent of choice for intervention in AD.

Growth hormone (GH) levels are blunted in obesity, but it is not known whether this relates to altered GH sensitivity and whether this influences the metabolic adaptation to fasting. Therefore, we investigated the effect of obesity on GH signal transduction and fasting-induced changes in GH action. Nine obese (BMI 35.7 kg/m2) and nine lean (BMI 21.5 kg/m2) men were studied in a randomized crossover design with 1) an intravenous GH bolus, 2) an intravenous saline bolus, and 3) 72 h of fasting. Insulin sensitivity (hyperinsulinemic, euglycemic clamp) and substrate metabolism (glucose tracer and indirect calorimetry) were measured in studies 1 and 2. In vivo GH signaling was assessed in muscle and fat biopsies. GH pharmacokinetics did not differ between obese and lean subjects, but endogenous GH levels were reduced in obesity. GH signaling (STAT5b phosphorylation and CISH mRNA transcription), and GH action (induction of lipolysis and peripheral insulin resistance) were similar in the two groups, but a GH-induced insulin antagonistic effect on endogenous glucose production only occurred in the obese. Fasting-induced IGF-I reduction was completely abrogated in obese subjects despite a comparable relative increase in GH levels (ΔIGF-I: lean, −66 ± 10 vs. obese, 27 ± 16 µg/l; P < 0.01; ΔGH: lean, 647 ± 280 vs. obese, 544 ± 220%; P = 0.76]. We conclude that 1) GH signaling is normal in obesity, 2) in the obese state, the preservation of IGF-I with fasting and the augmented GH-induced central insulin resistance indicate increased hepatic GH sensitivity, 3) blunted GH levels in obesity may protect against insulin resistance without compromising IGF-I status.