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We hypothesized that skeletal muscle contraction produces a cellular stress signal, triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying exercise-regulated myokines, also known as exerkines, able to promote lipolysis. Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. CM and human plasma samples were analyzed using unbiased proteomic screening and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples. CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes. Growth and differentiation factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was upregulated in CM from both acute and chronic exercise–stimulated myotubes. We further showed that physiological concentrations of recombinant GDF15 protein increased lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogated EPS CM-mediated lipolysis. We herein provide the first evidence to our knowledge that GDF15 is a potentially novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.

Abstract Context Exogenous ketone body administration lowers circulating glucose levels but the underlying mechanisms are uncertain. Objective We tested the hypothesis that administration of the ketone body β-hydroxybutyrate (βOHB) acutely increases insulin sensitivity via feedback suppression of circulating free fatty acid (FFA) levels. Methods In a randomized, single-blinded crossover design, 8 healthy men were studied twice with a growth hormone (GH) infusion to induce lipolysis in combination with infusion of either βOHB or saline. Each study day comprised a basal period and a hyperinsulinemic-euglycemic clamp combined with a glucose tracer and adipose tissue and skeletal muscle biopsies. Results βOHB administration profoundly suppressed FFA levels concomitantly with a significant increase in glucose disposal and energy expenditure. This was accompanied by a many-fold increase in skeletal muscle content of both βOHB and its derivative acetoacetate. Conclusion Our data unravel an insulin-sensitizing effect of βOHB, which we suggest is mediated by concomitant suppression of lipolysis.

Aims/hypothesisLack of insulin and infection/inflammation are the two most common causes of diabetic ketoacidosis (DKA). We used insulin withdrawal followed by insulin administration as a clinical model to define effects on substrate metabolism and to test whether increased levels of counter-regulatory hormones and cytokines and altered adipose tissue signalling participate in the early phases of DKA.MethodsNine individuals with type 1 diabetes, without complications, were randomly studied twice, in a crossover design, for 5 h followed by 2.5 h high-dose insulin clamp: (1) insulin-controlled euglycaemia (control) and (2) after 14 h of insulin withdrawal in a university hospital setting.ResultsInsulin withdrawal increased levels of glucose (6.1 ± 0.5 vs 18.6 ± 0.5 mmol/l), NEFA, 3-OHB (127 ± 18 vs 1837 ± 298 μmol/l), glucagon, cortisol and growth hormone and decreased HCO3− and pH, without affecting catecholamine or cytokine levels. Whole-body energy expenditure, endogenous glucose production (1.55 ± 0.13 vs 2.70 ± 0.31 mg kg−1 min−1), glucose turnover, non-oxidative glucose disposal, lipid oxidation, palmitate flux (73 [range 39–104] vs 239 [151–474] μmol/min), protein oxidation and phenylalanine flux all increased, whereas glucose oxidation decreased. In adipose tissue, Ser473 phosphorylation of Akt and mRNA levels of G0S2 decreased, whereas CGI-58 (also known as ABHD5) mRNA increased. Protein levels of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase phosphorylations were unaltered. Insulin therapy decreased plasma glucose concentrations dramatically after insulin withdrawal, without any detectable effect on net forearm glucose uptake.Conclusions/interpretationRelease of counter-regulatory hormones and overall increased catabolism, including lipolysis, are prominent features of preacidotic ketosis induced by insulin withdrawal, and dampening of Akt insulin signalling and transcriptional modulation of ATGL activity are involved. The lack of any increase in net forearm glucose uptake during insulin therapy after insulin withdrawal indicates muscle insulin resistance.Trial registrationClinicalTrials.gov NCT02077348FundingThis study was supported by Aarhus University and the KETO Study Group/Danish Agency for Science Technology and Innovation.

Background:Bariatric surgery remains the most effective treatment for reducing adiposity and eliminating type 2 diabetes; however, the mechanism(s) responsible have remained elusive. Peroxisome proliferator-activated receptors (PPAR) encompass a family of nuclear hormone receptors that upon activation exert control of lipid metabolism, glucose regulation and inflammation. Their role in adipose tissue following bariatric surgery remains undefined.Materials and Methods:Subcutaneous adipose tissue biopsies and serum were obtained and evaluated from time of surgery and on postoperative day 7 in patients randomized to Roux-en-Y gastric bypass (n=13) or matched caloric restriction (n=14), as well as patients undergoing vertical sleeve gastrectomy (n=33). Fat samples were evaluated for changes in gene expression, protein levels, β-oxidation, lipolysis and cysteine oxidation.Results:Within 7 days, bariatric surgery acutely drives a change in the activity and expression of PPARγ and PPARδ in subcutaneous adipose tissue thereby attenuating lipid storage, increasing lipolysis and potentiating lipid oxidation. This unique metabolic alteration leads to changes in downstream PPARγ/δ targets including decreased expression of fatty acid binding protein (FABP) 4 and stearoyl-CoA desaturase-1 (SCD1) with increased expression of carnitine palmitoyl transferase 1 (CPT1) and uncoupling protein 2 (UCP2). Increased expression of UCP2 not only facilitated fatty acid oxidation (increased 15-fold following surgery) but also regulated the subcutaneous adipose tissue redoxome by attenuating protein cysteine oxidation and reducing oxidative stress. The expression of UCP1, a mitochondrial protein responsible for the regulation of fatty acid oxidation and thermogenesis in beige and brown fat, was unaltered following surgery.Conclusions:These results suggest that bariatric surgery initiates a novel metabolic shift in subcutaneous adipose tissue to oxidize fatty acids independently from the beiging process through regulation of PPAR isoforms. Further studies are required to understand the contribution of this shift in expression of PPAR isoforms to weight loss following bariatric surgery.

Aims/hypothesis The aims of this study were to determine the role of lipolysis in hypoglycaemia and define the underlying intracellular mechanisms. Methods Nine healthy volunteers were randomised to treatment order of three different treatments (crossover design). Treatments were: (1) saline control; (2) hyperinsulinaemic hypoglycaemia (HH; i.v. bolus of 0.1 U/kg insulin); and (3) hyperinsulinaemic euglycaemia (HE; i.v. bolus of 0.1 U/kg insulin and 20% glucose). Inclusion criteria were that volunteers were healthy, aged >18 years, had a BMI between 19 and 26 kg/m 2 , and provided both written and oral informed consent. Exclusion criteria were the presence of a known chronic disease (including diabetes mellitus, epilepsy, ischaemic heart disease and cardiac arrhythmias) and regular use of prescription medication. The data was collected at the medical research facilities at Aarhus University Hospital, Denmark. The primary outcome was palmitic acid flux. Participants were blinded to intervention order, but caregivers were not. Results Adrenaline (epinephrine) and glucagon concentrations were higher during HH than during both HE and control treatments. NEFA levels and lipid oxidation rates (determined by indirect calorimetry) returned to control levels after 105 min. Palmitate flux was increased to control levels during HH ( p  = NS) and was more than twofold higher than during HE (overall mean difference between HH vs HE, 114 [95% CI 64, 165 μmol/min]; p  < 0.001). In subcutaneous adipose tissue biopsies, we found elevated levels of hormone-sensitive lipase (HSL) and perilipin-1 phosphorylation 30 min after insulin injection during HH compared with both control and HE. There were no changes in the levels of adipose triglyceride lipase (ATGL), comparative gene identification-58 (CGI-58) or G 0 /G 1 switch gene 2 (G0S2) proteins. Insulin-stimulated phosphorylation of Akt and mTOR were unaffected by hypoglycaemia. Expression of the G0S2 gene increased during HE and HH compared with control, without changes in ATGL (also known as PNPLA2 ) or CGI-58 (also known as ABHD5 ) mRNA levels. Conclusions/interpretation These findings suggest that NEFAs become a major fuel source during insulin-induced hypoglycaemia and that lipolysis may be an important component of the counter-regulatory response. These effects appear to be mediated by rapid stimulation of protein kinase A (PKA) and HSL, compatible with activation of the β-adrenergic catecholamine signalling pathway. Trial registration: ClinicalTrials.gov NCT01919788 Funding: The study was funded by Aarhus University, the Novo Nordisk Foundation and the KETO Study Group/Danish Agency for Science Technology and Innovation (grant no. 0603–00479, to NM).

The perception that intracellular lipolysis is a straightforward process that releases fatty acids from fat stores in adipose tissue to generate energy has experienced major revisions over the last two decades. The discovery of new lipolytic enzymes and coregulators, the demonstration that lipophagy and lysosomal lipolysis contribute to the degradation of cellular lipid stores and the characterization of numerous factors and signalling pathways that regulate lipid hydrolysis on transcriptional and post-transcriptional levels have revolutionized our understanding of lipolysis. In this review, we focus on the mechanisms that facilitate intracellular fatty-acid mobilization, drawing on canonical and noncanonical enzymatic pathways. We summarize how intracellular lipolysis affects lipid-mediated signalling, metabolic regulation and energy homeostasis in multiple organs. Finally, we examine how these processes affect pathogenesis and how lipolysis may be targeted to potentially prevent or treat various diseases. Zechner and colleagues discuss mechanisms facilitating the mobilization of intracellular fatty acids and how they affect lipid-mediated signalling, metabolic regulation and energy homeostasis in health and disease.

Objective: The melanocortin system has a highly significant role in the hypothalamic regulation of body weight and energy expenditure. In animals, intracerebroventricular infusion of melanocortin receptor 4 (MCR-4) agonists increases basal metabolic rate through activation of the sympathetic nervous system and subsequently reduces food intake. In humans, direct access of MCR-4 agonists to the central nervous system can be achieved by a transnasal route, which leads to weight loss with chronic administration. In the present study, we aimed at investigating the effects of intranasally administered MC4-R agonist MSH/ACTH(4–10) on lipolysis and sympathetic nervous system activity in healthy humans. Design: Healthy normal weight, male volunteers ( n =10) received either 10 mg MSH/ACTH(4–10) or placebo intranasally in a double-blinded randomized crossover design. Interstitial glycerol release was assessed by microdialysis in abdominal white adipose tissue (WAT) and in skeletal muscle (SM) of the forearm. Local blood flow, systemic blood pressure, heart rate and muscle sympathetic nerve activity (MSNA) within the superficial peroneal nerve were recorded at rest and after nitroprusside infusion. Results: At 45 min after MSH/ACTH(4–10) administration WAT glycerol concentrations increased by 53.4±19.3% compared with baseline conditions ( P <0.05) and remained significantly higher throughout the experiment when compared with placebo ( P <0.05) while local glycerol release in SM was not significantly affected. Resting MSNA was not altered by MSH/ACTH(4–10) administration; however, sympathoexcitation by intravenous nitroprusside was markedly elevated (MSH/ACTH(4–10) 569±69% increase to baseline; placebo: 315±64%; P <0.01). Conclusion: Intranasally administered MCR-4 agonist MSH/ACTH 4–10 increases both subcutaneous WAT lipolysis and MSNA, which suggests a direct central nervous peptide effect in humans on key factors of human energy metabolism.

Hormone-sensitive lipase (HSL) is a pivotal enzyme that mediates triglyceride hydrolysis to provide free fatty acids and glycerol in adipocytes in a hormonally controlled lipolysis process. Elevated plasma-free fatty acids were accompanied by insulin resistance, type-2 diabetes, and obesity. Inhibition of lipolysis through HSL inhibition may provide a mechanism to prevent the accumulation of free fatty acids and to improve the affectability of insulin and blood glucose handling in type II diabetes. The published studies that examine the structure, regulation, and function of HSL and major inhibitors were reviewed in this paper.

Lipids are essential building blocks synthesized by complex molecular pathways and deposited as lipid droplets (LDs) in cells. LDs are evolutionary conserved organelles found in almost all organisms, from bacteria to mammals. They are composed of a hydrophobic neutral lipid core surrounding by a phospholipid monolayer membrane with various decorating proteins. Degradation of LDs provide metabolic energy for divergent cellular processes such as membrane synthesis and molecular signaling. Lipolysis and autophagy are two main catabolic pathways of LDs, which regulate lipid metabolism and, thereby, closely engaged in many pathological conditons. In this review, we first provide an overview of the current knowledge on the structural properties and the biogenesis of LDs. We further focus on the recent findings of their catabolic mechanism by lipolysis and autophagy as well as their connection ragarding the regulation and function. Moreover, we discuss the relevance of LDs and their catabolism-dependent pathophysiological conditions.

The relationship between insulin resistance and visceral and muscle fat is complex. Recent research findings are unraveling some of the mysteries and suggesting therapeutic approaches to restoring insulin sensitivity. Type 2 diabetes currently affects more than a third of a billion people worldwide and is the leading cause of end-stage renal disease, nontraumatic loss of limb, and blindness in working adults, with estimated annual worldwide health care costs exceeding half a trillion dollars. 1 Furthermore, the worldwide prevalence of type 2 diabetes is projected to increase by more than 75% during the next two decades, with the largest increases occurring in Asia and the Indian subcontinent. 1 Although impaired beta-cell function is ultimately responsible for the progression from normoglycemia to hyperglycemia, insulin resistance predates beta-cell dysfunction and plays a major role . . .