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Introduction: Loss of skeletal muscle mass and function (sarcopenia) is common in individuals with obesity due to metabolic changes associated with a sedentary lifestyle, adipose tissue derangements, comorbidities (acute and chronic diseases) and during the ageing process. Co-existence of excess adiposity and low muscle mass/function is referred to as sarcopenic obesity (SO), a condition increasingly recognized for its clinical and functional features that negatively influence important patient-centred outcomes. Effective prevention and treatment strategies for SO are urgently needed, but efforts are hampered by the lack of a universally established SO definition and diagnostic criteria. Resulting inconsistencies in the literature also negatively affect the ability to define prevalence as well as clinical relevance of SO for negative health outcomes. Aims and Methods: The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) launched an initiative to reach expert consensus on a definition and diagnostic criteria for SO. The jointly appointed international expert panel proposes that SO is defined as the co-existence of excess adiposity and low muscle mass/function. The diagnosis of SO should be considered in at-risk individuals who screen positive for a co-occurring elevated body mass index or waist circumference, and markers of low skeletal muscle mass and function (risk factors, clinical symptoms, or validated questionnaires). Diagnostic procedures should initially include assessment of skeletal muscle function, followed by assessment of body composition where presence of excess adiposity and low skeletal muscle mass or related body compartments confirm the diagnosis of SO. Individuals with SO should be further stratified into stage I in the absence of clinical complications or stage II if cases are associated with complications linked to altered body composition or skeletal muscle dysfunction. Conclusions: ESPEN and EASO, as well as the expert international panel, advocate that the proposed SO definition and diagnostic criteria be implemented into routine clinical practice. The panel also encourages prospective studies in addition to secondary analysis of existing data sets, to study the predictive value, treatment efficacy and clinical impact of this SO definition.

To elucidate the molecular mechanisms underlying non‐alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome‐scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD + and glutathione (GSH) in subjects with high HS. Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD + repletion on the development of NAFLD, we added precursors for GSH and NAD + biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof‐of‐concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment. Synopsis Personalized modeling and metabolic measurements identified altered GSH and NAD + metabolism as a prevailing feature in NAFLD. These findings suggested a potential treatment strategy for NAFLD patients based on increased oxidation of fat and increased synthesis of GSH. We developed personalized genome‐scale metabolic models for NAFLD patients. We found that altered GSH and NAD + metabolism is a prevailing feature in NAFLD. Plasma and liver levels of glycine and serine were lower in NAFLD patients. Supplementation of precursors for glutathione and NAD + decreased HS in mice. Serine supplementation decreased liver fat and improved markers of liver function in humans. Graphical Abstract Personalized modeling and metabolic measurements identified altered GSH and NAD + metabolism as a prevailing feature in NAFLD. These findings suggested a potential treatment strategy for NAFLD patients based on increased oxidation of fat and increased synthesis of GSH.

White adipose tissue (WAT) inflammation contributes to the development of insulin resistance in obesity. While the role of adipose tissue macrophage (ATM) pro-inflammatory signalling in the development of insulin resistance has been established, it is less clear how WAT inflammation is initiated. Here, we show that ATMs isolated from obese mice and humans exhibit markers of increased rate of de novo phosphatidylcholine (PC) biosynthesis. Macrophage-specific knockout of phosphocholine cytidylyltransferase A (CCTα), the rate-limiting enzyme of de novo PC biosynthesis pathway, alleviated obesity-induced WAT inflammation and insulin resistance. Mechanistically, CCTα-deficient macrophages showed reduced ER stress and inflammation in response to palmitate. Surprisingly, this was not due to lower exogenous palmitate incorporation into cellular PCs. Instead, CCTα-null macrophages had lower membrane PC turnover, leading to elevated membrane polyunsaturated fatty acid levels that negated the pro-inflammatory effects of palmitate. Our results reveal a causal link between obesity-associated increase in de novo PC synthesis, accelerated PC turnover and pro-inflammatory activation of ATMs. Although inflammation can be good for the body and help fight off infection, in certain cases it can also be harmful. When immune cells switch on at the wrong time, they can cause damage to cells and tissues. Fat tissue has its own population of immune cells called adipose tissue macrophages that remove dead fat cells and keep the tissue working. However, obesity changes the behaviour of these macrophages so they switch on as though they were fighting an infection and make the fat tissue inflamed. The signals produced by these activated macrophages stop fat tissue working, and this can lead to type 2 diabetes. The trigger that activates macrophages in obesity is not yet clear, but some evidence suggests that it is due to the type of fat available. Fats come in two main forms: saturated, which can lead to high cholesterol, or unsaturated which can reduce the risk of high blood pressure. An increase in saturated fats can cause cells, including macrophages, to become stressed. Researchers showed in 2011 that macrophages in the fatty tissue of obese mice accumulate fat and become inflamed, but it was unclear which types of fat, if any, were driving the inflammation. Now, Petkevicius et al. – including some of the researchers involved in the 2011 work – report that macrophages in the fatty tissue of obese mice make excess phosphatidylcholine, a fat normally found in the cell membrane. Phosphatidylcholine is a type of fat known as a phospholipid and it is made up of two subunits called fatty acids that can either be saturated or unsaturated. In obese people and mice, fatty tissue produces too much of the enzyme that makes phosphatidylcholine, called CCTa. Petkevicius et al. showed that partially removing the CCTa gene from macrophages reduces inflammation, but, unexpectedly, the amount of phosphatidylcholine in the cells stays the same. This is because macrophages respond to the halt in phosphatidylcholine production by removing less of the phospholipid from the membrane. This gives the macrophages time to exchange the saturated fatty acids in phosphatidylcholine for unsaturated fatty acids. Therefore, the longer phosphatidylcholine stays in the membrane, the more likely it is to contain unsaturated fatty acids. Further experiments demonstrated that this change counteracts the effects caused by excess saturated fats, protecting the cells and reducing inflammation. Although the understanding of obesity is still in its early stages, this study adds another piece of the puzzle. If we can understand why fat stops working in obesity, and how this leads to disease, it could aid the design of new treatments for type 2 diabetes.

Increased fructose consumption has been suggested to contribute to non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and insulin resistance, but a causal role of fructose in these metabolic diseases remains debated. Mechanistically, hepatic fructose metabolism yields precursors that can be used for gluconeogenesis and de novo lipogenesis (DNL). Fructose-derived precursors also act as nutritional regulators of the transcription factors, including ChREBP and SREBP1c, that regulate the expression of hepatic gluconeogenesis and DNL genes. In support of these mechanisms, fructose intake increases hepatic gluconeogenesis and DNL and raises plasma glucose and triglyceride levels in humans. However, epidemiological and fructose-intervention studies have had inconclusive results with respect to liver fat, and there is currently no good human evidence that fructose, when consumed in isocaloric amounts, causes more liver fat accumulation than other energy-dense nutrients. In this review, we aim to provide an overview of the seemingly contradicting literature on fructose and NAFLD. We outline fructose physiology, the mechanisms that link fructose to NAFLD, and the available evidence from human studies. From this framework, we conclude that the cellular mechanisms underlying hepatic fructose metabolism will likely reveal novel targets for the treatment of NAFLD, dyslipidemia, and hepatic insulin resistance. Finally, fructose-containing sugars are a major source of excess calories, suggesting that a reduction of their intake has potential for the prevention of NAFLD and other obesity-related diseases.

A Major Role for Perifornical Orexin Neurons in the Control of Glucose Metabolism in Rats Chun-Xia Yi 1 , Mireille J. Serlie 2 , Mariette T. Ackermans 3 , Ewout Foppen 1 , 2 , Ruud M. Buijs 4 , Hans P. Sauerwein 2 , Eric Fliers 2 and Andries Kalsbeek 1 , 2 1 Department of Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands; 2 Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 3 Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 4 Instituto de Investigaciones Biomedicas Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City, Mexico. Corresponding author: Chun-Xia Yi, c.yi{at}nin.knaw.nl . Abstract OBJECTIVE The hypothalamic neuropeptide orexin influences (feeding) behavior as well as energy metabolism. Administration of exogenous orexin-A into the brain has been shown to increase both food intake and blood glucose levels. In the present study, we investigated the role of endogenous hypothalamic orexin release in glucose homeostasis in rats. RESEARCH DESIGN AND METHODS We investigated the effects of the hypothalamic orexin system on basal endogenous glucose production (EGP) as well as on hepatic and peripheral insulin sensitivity by changing orexinergic activity in the hypothalamus combined with hepatic sympathetic or parasympathetic denervation, two-step hyperinsulinemic-euglycemic clamps, immunohistochemistry, and RT-PCR studies. RESULTS Hypothalamic disinhibition of neuronal activity by the γ-aminobutyric acid receptor antagonist bicuculline (BIC) increased basal EGP, especially when BIC was administered in the perifornical area where orexin-containing neurons but not melanocortin-concentrating hormone–containing neurons were activated. The increased BIC-induced EGP was largely prevented by intracerebroventricular pretreatment with the orexin-1 receptor antagonist. Intracerebroventricular administration of orexin-A itself caused an increase in plasma glucose and prevented the daytime decrease of EGP. The stimulatory effect of intracerebroventricular orexin-A on EGP was prevented by hepatic sympathetic denervation. Plasma insulin clamped at two or six times the basal levels did not counteract the stimulatory effect of perifornical BIC on EGP, indicating hepatic insulin resistance. RT-PCR showed that stimulation of orexin neurons increased the expression of hepatic glucoregulatory enzymes. CONCLUSIONS Hypothalamic orexin plays an important role in EGP, most likely by changing the hypothalamic output to the autonomic nervous system. Disturbance of this pathway may result in unbalanced glucose homeostasis. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received March 13, 2009. Accepted June 9, 2009. © 2009 by the American Diabetes Association.

Pharmacological Inhibition of Glucosylceramide Synthase Enhances Insulin Sensitivity Johannes M. Aerts 1 , Roelof Ottenhoff 2 , Andrew S. Powlson 3 , Aldo Grefhorst 4 , Marco van Eijk 2 , Peter F. Dubbelhuis 2 , Jan Aten 4 , Folkert Kuipers 5 , Mireille J. Serlie 6 , Tom Wennekes 7 , Jaswinder K. Sethi 3 , Stephen O'Rahilly 3 and Hermen S. Overkleeft 7 1 Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 2 Macrozyme, Amsterdam, the Netherlands 3 Department of Clinical Biochemistry, University of Cambridge, Cambridge, U.K 4 Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 5 Centre for Liver, Digestive, and Metabolic Disease, Academic Hospital Groningen, University of Groningen, Groningen, the Netherlands 6 Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 7 Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands Address correspondence and reprint requests to J.M. Aerts, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105AZ, Amsterdam, Netherlands. E-mail: j.m.aerts{at}amc.uva.nl Abstract A growing body of evidence implicates ceramide and/or its glycosphingolipid metabolites in the pathogenesis of insulin resistance. We have developed a highly specific small molecule inhibitor of glucosylceramide synthase, an enzyme that catalyzes a necessary step in the conversion of ceramide to glycosphingolipids. In cultured 3T3-L1 adipocytes, the iminosugar derivative N -(5′-adamantane-1′-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM) counteracted tumor necrosis factor-α–induced abnormalities in glycosphingolipid concentrations and concomitantly reversed abnormalities in insulin signal transduction. When administered to mice and rats, AMP-DNM significantly reduced glycosphingolipid but not ceramide concentrations in various tissues. Treatment of ob/ob mice with AMP-DNM normalized their elevated tissue glucosylceramide levels, markedly lowered circulating glucose levels, improved oral glucose tolerance, reduced A1C, and improved insulin sensitivity in muscle and liver. Similarly beneficial metabolic effects were seen in high fat–fed mice and ZDF rats. These findings provide further evidence that glycosphingolipid metabolites of ceramide may be involved in mediating the link between obesity and insulin resistance and that interference with glycosphingolipid biosynthesis might present a novel approach to the therapy of states of impaired insulin action such as type 2 diabetes. AMP-DNM, N-(5′-adamantane-1′-yl-methoxy)-pentyl-1-deoxynojirimycin AUC, area under the curve GM3, sialosyllactosylceramide HPLC, high-performance liquid chromatography HRP, horseradish peroxidase PDMP, 1-phenyl-2-decanoylamino-3-morpholinopropanol TNF, tumor necrosis factor Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 7 February 2007. DOI: 10.2337/db06-1619. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1619 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted February 1, 2007. Received November 18, 2006. DIABETES

IntroductionMetabolic bariatric surgery (MBS) can lead to substantial fat-free mass loss (FFML) due to malnutrition, decreased protein intake and insufficient physical activity. Disproportional FFML has been associated with an increased risk for adverse health outcomes. Resistance training (RT) combined with protein intake contributes to maintenance and increase of fat-free mass (FFM) in healthy individuals. However, it is unclear whether RT and protein supplementation can prevent FFML after MBS.Methods and analysisIn the EffectiveNess of pRotein supplementatIon Combined witH resistance Exercise training to counteract Disproportional fat-free mass loss following metabolic bariatric surgery (ENRICHED) randomised controlled trial, 400 patients scheduled to undergo MBS will be randomised in a 1:1 ratio to the ENRICHED perioperative care programme (intervention group) or the standard perioperative care programme of the Dutch Obesity Clinic (control group). The study is currently recruiting participants at two centres in the Netherlands: Nieuwegein and Amsterdam. The postoperative standard programme consists of 13 group sessions spread over a period of 18 months. As part of the ENRICHED programme, RT and protein supplementation will be added 3 weeks after MBS. Additional whole-body RT consists of home-based training sessions two to three times a week, and supervised RT sessions of 45–60 min once weekly, performed at 60–75% of one-repetition maximum (1-RM). Protein supplementation will start by adding 20 g of whey protein to the daily intake. The supplementation will be gradually increased with 20 g every 4 weeks until a total of 60 g whey protein a day is reached. After 12 weeks of protein supplementation, the focus shifts towards incorporating protein-rich food products into the daily dietary intake. The primary endpoint is the prevalence of disproportional FFM loss, defined as FFML/total weight loss ≥30%, at 3 months post-MBS. Secondary endpoints are differences in body composition, muscle strength and function, cardiorespiratory fitness, (cardio)metabolic health, health-related quality of life, gastrointestinal discomfort, cost-effectiveness of the intervention and treatment satisfaction. Outcomes will be assessed preoperatively and at 3, 6 and 12 months postoperatively.Ethics and disseminationThe study protocol V.2.0 was approved by the Medical Research Ethics Committee Oost-Nederland (NL-OMON57119) on 9 April 2025. All participants will provide written informed consent prior to enrolment. Study findings will be disseminated through peer-reviewed publications and conference presentations. Insights gained in this study will provide evidence for a patient-tailored intervention that could be implemented in clinical practice.Trial registration number NCT07156552.

Thyrotoxicosis increases endogenous glucose production (EGP) and induces hepatic insulin resistance. We have recently shown that these alterations can be modulated by selective hepatic sympathetic and parasympathetic denervation, pointing to neurally mediated effects of thyroid hormone on glucose metabolism. Here, we investigated the effects of central triiodothyronine (T₃) administration on EGP. We used stable isotope dilution to measure EGP before and after i.c.v. bolus infusion of T₃ or vehicle in euthyroid rats. To study the role of hypothalamic preautonomic neurons, bilateral T₃ microdialysis in the paraventricular nucleus (PVN) was performed for 2 h. Finally, we combined T₃ microdialysis in the PVN with selective hepatic sympathetic denervation to delineate the involvement of the sympathetic nervous system in the observed metabolic alterations. T₃ microdialysis in the PVN increased EGP by 11 ± 4% (P = 0.020), while EGP decreased by 5 ± 8% (ns) in vehicle-treated rats (T₃ vs. Veh, P = 0.030). Plasma glucose increased by 29 ± 5% (P = 0.0001) after T₃ microdialysis versus 8 ± 3% in vehicle-treated rats (T₃ vs. Veh, P = 0.003). Similar effects were observed after i.c.v. T₃ administration. Effects of PVN T₃ microdialysis were independent of plasma T₃, insulin, glucagon, and corticosterone. However, selective hepatic sympathectomy completely prevented the effect of T₃ microdialysis on EGP. We conclude that stimulation of T₃-sensitive neurons in the PVN of euthyroid rats increases EGP via sympathetic projections to the liver, independently of circulating glucoregulatory hormones. This represents a unique central pathway for modulation of hepatic glucose metabolism by thyroid hormone.

ObjectiveBariatric surgery improves glucose metabolism. Recent data suggest that faecal microbiota transplantation (FMT) using faeces from postbariatric surgery diet-induced obese mice in germ-free mice improves glucose metabolism and intestinal homeostasis. We here investigated whether allogenic FMT using faeces from post-Roux-en-Y gastric bypass donors (RYGB-D) compared with using faeces from metabolic syndrome donors (METS-D) has short-term effects on glucose metabolism, intestinal transit time and adipose tissue inflammation in treatment-naïve, obese, insulin-resistant male subjects.DesignSubjects with metabolic syndrome (n=22) received allogenic FMT either from RYGB-D or METS-D. Hepatic and peripheral insulin sensitivity as well as lipolysis were measured at baseline and 2 weeks after FMT by hyperinsulinaemic euglycaemic stable isotope (2H2-glucose and 2H5-glycerol) clamp. Secondary outcome parameters were changes in resting energy expenditure, intestinal transit time, faecal short-chain fatty acids (SCFA) and bile acids, and inflammatory markers in subcutaneous adipose tissue related to intestinal microbiota composition. Faecal SCFA, bile acids, glycaemic control and inflammatory parameters were also evaluated at 8 weeks.ResultsWe observed a significant decrease in insulin sensitivity 2 weeks after allogenic METS-D FMT (median rate of glucose disappearance: from 40.6 to 34.0 µmol/kg/min; p<0.01). Moreover, a trend (p=0.052) towards faster intestinal transit time following RYGB-D FMT was seen. Finally, we observed changes in faecal bile acids (increased lithocholic, deoxycholic and (iso)lithocholic acid after METS-D FMT), inflammatory markers (decreased adipose tissue chemokine ligand 2 (CCL2) gene expression and plasma CCL2 after RYGB-D FMT) and changes in several intestinal microbiota taxa.ConclusionAllogenic FMT using METS-D decreases insulin sensitivity in metabolic syndrome recipients when compared with using post-RYGB-D. Further research is needed to delineate the role of donor characteristics in FMT efficacy in human insulin-resistant subjects.Trial registration numberNTR4327.

Glucocorticoid receptors are highly expressed in the hypothalamic paraventricular nucleus (PVN) and arcuate nucleus (ARC). As glucocorticoids have pronounced effects on neuropeptide Y (NPY) expression and as NPY neurons projecting from the ARC to the PVN are pivotal for balancing feeding behavior and glucose metabolism, we investigated the effect of glucocorticoid signaling in these areas on endogenous glucose production (EGP) and insulin sensitivity by local retrodialysis of the glucocorticoid receptor agonist dexamethasone into the ARC or the PVN, in combination with isotope dilution and hyperinsulinemic-euglycemic clamp techniques. Retrodialysis of dexamethasone for 90 min into the ARC or the PVN did not have significant effects on basal plasma glucose concentration. During the hyperinsulinemic-euglycemic clamp, retrodialysis of dexamethasone into the ARC largely prevented the suppressive effect of hyperinsulinemia on EGP. Antagonizing the NPY1 receptors by intracerebroventricular infusion of its antagonist largely blocked the hepatic insulin resistance induced by dexamethasone in the ARC. The dexamethasone-ARC-induced inhibition of hepatic insulin sensitivity was also prevented by hepatic sympathetic denervation. These data suggest that glucocorticoid signaling specifically in the ARC neurons modulates hepatic insulin responsiveness via NPY and the sympathetic system, which may add to our understanding of the metabolic impact of clinical conditions associated with hypercortisolism.