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Five-year data showed that among patients with type 2 diabetes and a BMI of 27 to 43, bariatric surgery plus intensive medical therapy was more effective than intensive medical therapy alone in decreasing or resolving hyperglycemia, even among those with a BMI of less than 35. Observational studies 1 – 6 and randomized, controlled trials, which have generally been short-term studies, 7 – 19 have shown that bariatric surgery, when used specifically to treat diabetes, significantly improves glycemic control and reduces cardiovascular risk factors. In the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial, we reported that, at 1 year and 3 years after randomization, both gastric bypass and sleeve gastrectomy were superior to intensive medical therapy alone in achieving excellent glycemic control (i.e., glycated hemoglobin ≤6.0%), reducing cardiovascular risk, improving quality of life, and decreasing medication use. 8 – 10 The current article provides results of the final, 5-year . . .

Cardiovascular disease (CVD) is a serious comorbidity in nonalcoholic fatty liver disease (NAFLD). Since plasma ceramides are increased in NAFLD and sphingomyelin, a ceramide metabolite, is an independent risk factor for CVD, the role of ceramides in dyslipidemia was assessed using LDLR(-/-) mice, a diet-induced model of NAFLD and atherosclerosis. Mice were fed a standard or Western diet (WD), with or without myriocin, an inhibitor of ceramide synthesis. Hepatic and plasma ceramides were profiled and lipid and lipoprotein kinetics were quantified. Hepatic and intestinal expression of genes and proteins involved in insulin, lipid and lipoprotein metabolism were also determined. WD caused hepatic oxidative stress, inflammation, apoptosis, increased hepatic long-chain ceramides associated with apoptosis (C16 and C18) and decreased very-long-chain ceramide C24 involved in insulin signaling. The plasma ratio of ApoB/ApoA1 (proteins of VLDL/LDL and HDL) was increased 2-fold due to increased ApoB production. Myriocin reduced hepatic and plasma ceramides and sphingomyelin, and decreased atherosclerosis, hepatic steatosis, fibrosis, and apoptosis without any effect on oxidative stress. These changes were associated with decreased lipogenesis, ApoB production and increased HDL turnover. Thus, modulation of ceramide synthesis may lead to the development of novel strategies for the treatment of both NAFLD and its associated atherosclerosis.

The SARS-CoV-2 pandemic continues to rage around the world. At the same time, despite strong public health measures and high vaccination rates in some countries, a post-COVID-19 syndrome has emerged which lacks a clear definition, prevalence, or etiology. However, fatigue, dyspnea, brain fog, and lack of smell and/or taste are often characteristic of patients with this syndrome. These are evident more than a month after infection, and are labeled as Post-Acute Sequelae of CoV-2 (PASC) or commonly referred to as long-COVID. Metabolic dysfunction (i.e., obesity, insulin resistance, and diabetes mellitus) is a predisposing risk factor for severe acute COVID-19, and there is emerging evidence that this factor plus a chronic inflammatory state may predispose to PASC. In this article, we explore the potential pathogenic metabolic mechanisms that could underly both severe acute COVID-19 and PASC, and then consider how these might be targeted for future therapeutic approaches.

At 3 years of follow-up, among obese patients with uncontrolled type 2 diabetes who were randomly assigned to receive intensive medical therapy with or without bariatric surgery, significantly more patients in the surgery groups achieved glycemic control. Bariatric surgery has recently emerged as a potentially useful treatment for type 2 diabetes mellitus. 1 Observational studies 2 – 5 and randomized, controlled trials 6 – 10 have shown that procedures including Roux-en-Y gastric bypass, sleeve gastrectomy, gastric banding, and biliopancreatic diversion significantly improve glycemic control and favorably affect cardiovascular risk factors. In the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial, we found that 1 year after randomization, gastric bypass and sleeve gastrectomy were superior to intensive medical therapy alone in achieving glycemic control and reducing cardiovascular risk factors while decreasing dependency on pharmacotherapy for diabetes management. 7 Although bariatric surgery yields . . .

Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia. Cancer-associated cachexia is characterized by loss of body weight, skeletal muscle and adipose tissue which relates to higher mortality in cancer patients. Here, the authors show in a lung cancer murine model that both ActRIIB signalling inhibition and restoring appetite are necessary to revert cachexia and improve survival in female mice.

Plasma Ceramides Are Elevated in Obese Subjects With Type 2 Diabetes and Correlate With the Severity of Insulin Resistance Jacob M. Haus 1 2 , Sangeeta R. Kashyap 3 , Takhar Kasumov 4 , Renliang Zhang 5 , Karen R. Kelly 1 6 , Ralph A. DeFronzo 7 and John P. Kirwan 1 2 4 6 1 Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 2 Department of Physiology, Case Western Reserve University School of Medicine, Cleveland, Ohio 3 Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic, Cleveland, Ohio 4 Department of Gastroenterology/Hepatology, Cleveland Clinic, Cleveland, Ohio 5 Department of Cardiovascular Medicine and Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 6 Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio 7 Division of Diabetes, University of Texas Health Science Center, San Antonio, Texas Corresponding author: John P. Kirwan, kirwanj{at}ccf.org Abstract OBJECTIVE— To quantitate plasma ceramide subspecies concentrations in obese subjects with type 2 diabetes and relate these plasma levels to the severity of insulin resistance. Ceramides are a putative mediator of insulin resistance and lipotoxicity, and accumulation of ceramides within tissues in obese and diabetic subjects has been well described. RESEARCH DESIGN AND METHODS— We analyzed fasting plasma ceramide subspecies by quantitative tandem mass spectrometry in 13 obese type 2 diabetic patients and 14 lean healthy control subjects. Results were related to insulin sensitivity measured with the hyperinsulinemic-euglycemic clamp technique and with plasma tumor necrosis factor-α (TNF-α) levels, a marker of inflammation. Ceramide species (C18:1, 18:0, 20:0, 24:1, and 24:0) were quantified using electrospray ionization tandem mass spectrometry after separation with high-performance liquid chromatography. RESULTS— Insulin sensitivity (mg · kg −1 · min −1 ) was lower in type 2 diabetic patients (4.90 ± 0.3) versus control subjects (9.6 ± 0.4) ( P < 0.0001). Type 2 diabetic subjects had higher ( P < 0.05) concentrations of C18:0, C20:0, C24:1, and total ceramide. Insulin sensitivity was inversely correlated with C18:0, C20:0, C24:1, C24:0, and total ceramide (all P < 0.01). Plasma TNF-α concentration was increased ( P < 0.05) in type 2 diabetic subjects and correlated with increased C18:1 and C18:0 ceramide subspecies. CONCLUSIONS— Plasma ceramide levels are elevated in type 2 diabetic subjects and may contribute to insulin resistance through activation of inflammatory mediators, such as TNF-α. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 13 November 2008. J.M.H., and S.R.K. contributed equally to this work. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. 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 November 5, 2008. Received September 4, 2008. DIABETES

Background Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial‐targeted furazano[3,4‐b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet‐induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity. Methods Eighty‐week‐old male C57BL/6J mice with obesity were randomized to 10 weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w/w in high fat diet) treatment. Body weight and food intake were measured weekly. Body composition, muscle function, energy expenditure, locomotor activity, and glucose tolerance were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signalling, and mitochondrial structure and function. Results BAM15 decreased body weight (54.0 ± 2.0 vs. 42.3 ± 1.3 g, P < 0.001) which was attributable to increased energy expenditure (10.1 ± 0.1 vs. 11.3 ± 0.4 kcal/day, P < 0.001). BAM15 increased muscle mass (52.7 ± 0.4 vs. 59.4 ± 1.0%, P < 0.001), strength (91.1 ± 1.3 vs. 124.9 ± 1.2 g, P < 0.0001), and locomotor activity (347.0 ± 14.4 vs. 432.7 ± 32.0 m, P < 0.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (interleukin 6 and gp130, both P < 0.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control (PINK1‐ubiquitin binding and LC3II, P < 0.01), increased mitochondrial activity (citrate synthase and complex II activity, all P < 0.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble/soluble ratio, P < 0.0001) while limiting ER stress (decreased PERK signalling, P < 0.0001), apoptotic signalling (decreased cytochrome C release and Caspase‐3/9 activation, all P < 0.001), and muscle protein degradation (decreased 14‐kDa actin fragment insoluble/soluble ratio, P < 0.001). Conclusions Mitochondrial uncoupling by agents such as BAM15 may mitigate age‐related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity.

Infusion of TNF-α results in increased insulin resistance in rat and human skeletal muscle cells incubated in culture (21), although TNF-α neutralization over a period of 4 weeks had no effect on insulin sensitivity in obese type 2 diabetic subjects (22). The role of excess lipid turnover and cytokine production from adipose tissue, especially in obese patients, could potentially be very important in the overall insulin resistance and excess substrate supply that drives maternal-fetal energy transfer and increased neonatal adiposity.

Obesity is a leading cause of preventable death worldwide. Despite this, current strategies for the treatment of obesity remain ineffective at achieving long‐term weight control. This is due, in part, to difficulties in identifying tolerable and efficacious small molecules or biologics capable of regulating systemic nutrient homeostasis. Here, we demonstrate that BAM15, a mitochondrially targeted small molecule protonophore, stimulates energy expenditure and glucose and lipid metabolism to protect against diet‐induced obesity. Exposure to BAM15 in vitro enhanced mitochondrial respiratory kinetics, improved insulin action, and stimulated nutrient uptake by sustained activation of AMPK. C57BL/6J mice treated with BAM15 were resistant to weight gain. Furthermore, BAM15‐treated mice exhibited improved body composition and glycemic control independent of weight loss, effects attributable to drug targeting of lipid‐rich tissues. We provide the first phenotypic characterization and demonstration of pre‐clinical efficacy for BAM15 as a pharmacological approach for the treatment of obesity and related diseases. Synopsis This study presents a novel therapy for treatment of obesity‐related diseases. Oral delivery of the mitochondrial protonophore BAM15 markedly reduced weight gain and fat accrual while improving glycemic control. BAM15 displays extended mitochondrial activity compared to previous generation protonophores. BAM15 protects against diet induced obesity. BAM15 modulates body composition and glycemic control independently of its weight‐reducing effects. AMPK is required to sustain the metabolic benefit of BAM15, which occurs primarily in adipose tissue. Graphical Abstract This study presents a novel therapy for treatment of obesity‐related diseases. Oral delivery of the mitochondrial protonophore BAM15 markedly reduced weight gain and fat accrual while improving glycemic control.

Loss of protein and organelle quality control secondary to reduced autophagy is a hallmark of aging. However, the physiologic and molecular regulation of autophagy in long-lived organisms remains incompletely understood. Here we show that the Kruppel-like family of transcription factors are important regulators of autophagy and healthspan in C. elegans , and also modulate mammalian vascular age-associated phenotypes. Kruppel-like family of transcription factor deficiency attenuates autophagy and lifespan extension across mechanistically distinct longevity nematode models. Conversely, Kruppel-like family of transcription factor overexpression extends nematode lifespan in an autophagy-dependent manner. Furthermore, we show the mammalian vascular factor Kruppel-like family of transcription factor 4 has a conserved role in augmenting autophagy and improving vessel function in aged mice. Kruppel-like family of transcription factor 4 expression also decreases with age in human vascular endothelium. Thus, Kruppel-like family of transcription factors constitute a transcriptional regulatory point for the modulation of autophagy and longevity in C. elegans with conserved effects in the murine vasculature and potential implications for mammalian vascular aging. KLF family transcription factors (KLFs) regulate many cellular processes, including proliferation, survival and stress responses. Here, the authors position KLFs as important regulators of autophagy and lifespan in C. elegans , a role that may extend to the modulation of age-associated vascular phenotypes in mammals.