Concurrent betaine administration enhances exercise-induced improvements to glucose handling in obese mice

Background and aimsBetaine supplementation has been shown to enhance hepatic lipid metabolism in obese mice and improve exercise performance in healthy populations. We examined effects of betaine supplementation, alone or in combination with treadmill exercise, on the metabolic consequences of high fat diet (HFD)-induced obesity in mice.Methods and resultsMale C57BL/6 J mice were fed chow or HFD. After 15 weeks, HFD mice were split into: HFD, HFD with betaine (1.5% w/v), HFD with treadmill exercise, and HFD with both betaine and exercise (15 m/min for 45min, 6 days/week; n = 12/group) for 10 weeks. Compared to HFD mice, body weight was significantly reduced in exercise and exercise-betaine mice, but not in mice given betaine alone. Similarly, adiposity was reduced by exercise but not by betaine alone. HFD-induced glucose intolerance was slightly improved by exercise, but not with betaine alone.Significantly greater benefits were observed in exercise-betaine mice, compared to exercise alone, such that GTT-outcomes were similar to controls. This was associated with reduced insulin levels during ipGTT, suggesting enhanced insulin sensitivity. Modest benefits were observed in fatty acid metabolism genes in skeletal muscle, whilst limited effects were observed in the liver. HFD-induced increases in hepatic Mpc1 (mitochondrial pyruvate carrier 1) were normalized by all treatments, suggesting potential links to altered glucose metabolism.ConclusionsOur data show that drinking 1.5% betaine was sufficient to augment metabolic benefits of exercise in obese mice. These processes appear to be facilitated by altered glucose metabolism, with limited effects on hepatic lipid metabolism.     

Obesity,diabetes, and the gut microbiome: an updated review

Introduction: Obesity and diabetes are two of the most prevalent health problems and leading causes of death globally. As research on the intestinal microbiome increases, so does our understanding of its intricate relationship to these diseases, although this has yet to be fully elucidated.

Areas covered: This review evaluates the role of the gut microbiome in obesity and diabetes, including the influences of internal and environmental factors. Literature searches were performed using the keywords ‘diabetes,’ ‘insulin resistance,’ ‘gut microbiome,’ ‘gut microbes,’ ‘obesity,’ and ‘weight gain.’

Expert commentary: Highlights of recent research include new findings regarding the effects of caloric restriction, which expound the importance of diet in shaping the gut microbiome, and studies reinforcing the lasting implications of antibiotic use for diabetes and obesity, particularly repeated doses in early childhood.

Mechanistically, interactions between the microbiome and the host innate immune system, mediated by TLR4-LPS signaling, have been shown to meditate the metabolic benefits of caloric restriction. Further, gut microbes haven now been shown to regulate oxygen availability via butyrate production, thus protecting against the proliferation of pathogens such as E. coli and Salmonella. However, many microbial metabolites remain unidentified and their roles in obesity and diabetes remain to be determined.     

Brown adipose tissue thermogenesis in humans

The prevalence of obesity and type 2 diabetes is at epidemic proportions. Classical interventions aimed at targeting obesity, such as reducing energy intake or increasing exercise, are often not effective over the long term. In contrast to white adipocytes, which store energy, brown adipocytes generate heat via mitochondrial uncoupling protein 1, thereby acting as a defence against hypothermia and, potentially, obesity. In this issue of Diabetologia, Admiraal et al compare brown adipose tissue activation during cold exposure between two different ethnic groups: South Asians and Europids. The prevalence of abdominal obesity and type 2 diabetes differs among various ethnic groups and decreased BAT metabolic activity could be one causal factor. As yet, the clinical impact of this ‘rediscovered’ organ is largely unknown, but has potential as a drug target for obesity.     

AMP活化蛋白激酶研究进展

能量代谢失衡是肥胖、糖尿病及代谢综合征的主要原因.AMP活化蛋白激酶(AMPK)是一种重要的蛋白激酶,可以调节能量代谢,开启分解代谢途径,如脂肪酸氧化和糖酵解,从而增加ATP的产生,同时关闭合成代谢途径,如多种脂类、蛋白质及糖原的合成,减少ATP的消耗.在增加骨骼肌对匍萄糖的摄取、增强胰岛素敏感性、增加脂肪酸氧化以及调节基因转录等方面发挥重要作用.AMPK不仅町以在细胞水平作为"能量调节器",在整体水平还可以通过激素和细胞因子,如瘦素、脂联素和ghrelin调节机体的能量代谢.凼而,阐明AMPK在不同组织细胞及整体水平上调节糖脂代谢的机制是今后该领域的研究热点,也是临床治疗肥胖、2型糖尿病及代谢综合征等疾病的有效靶点.     

AMP活化蛋白激酶研究进展

能量代谢失衡是肥胖、糖尿病及代谢综合征的主要原因.AMP活化蛋白激酶(AMPK)是一种重要的蛋白激酶,可以调节能量代谢,开启分解代谢途径,如脂肪酸氧化和糖酵解,从而增加ATP的产生,同时关闭合成代谢途径,如多种脂类、蛋白质及糖原的合成,减少ATP的消耗.在增加骨骼肌对匍萄糖的摄取、增强胰岛素敏感性、增加脂肪酸氧化以及调节基因转录等方面发挥重要作用.AMPK不仅町以在细胞水平作为"能量调节器",在整体水平还可以通过激素和细胞因子,如瘦素、脂联素和ghrelin调节机体的能量代谢.凼而,阐明AMPK在不同组织细胞及整体水平上调节糖脂代谢的机制是今后该领域的研究热点,也是临床治疗肥胖、2型糖尿病及代谢综合征等疾病的有效靶点.     

AMP活化蛋白激酶研究进展

能量代谢失衡是肥胖、糖尿病及代谢综合征的主要原因.AMP活化蛋白激酶(AMPK)是一种重要的蛋白激酶,可以调节能量代谢,开启分解代谢途径,如脂肪酸氧化和糖酵解,从而增加ATP的产生,同时关闭合成代谢途径,如多种脂类、蛋白质及糖原的合成,减少ATP的消耗.在增加骨骼肌对匍萄糖的摄取、增强胰岛素敏感性、增加脂肪酸氧化以及调节基因转录等方面发挥重要作用.AMPK不仅町以在细胞水平作为"能量调节器",在整体水平还可以通过激素和细胞因子,如瘦素、脂联素和ghrelin调节机体的能量代谢.凼而,阐明AMPK在不同组织细胞及整体水平上调节糖脂代谢的机制是今后该领域的研究热点,也是临床治疗肥胖、2型糖尿病及代谢综合征等疾病的有效靶点.     

Gut microbiota and physical exercise in obesity and diabetes – A systematic review

Background and aimThe gut microbiota (GM) plays an essential role in maintaining health, and imbalance in its composition is associated with the physiopathogenesis of metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Diet and antibiotics are known modulators of GM, but the influence of physical exercise in modulating the diversity and abundance of hindgut bacteria is still poorly understood. The aim of this systematic review was to investigate the scientific evidence about the effect of physical exercise on GM modulation in subjects with obesity and T2DM.Methods and resultsA search in PubMed, Web of Science, Scopus, Cochrane and Embase databases using keywords related to gut microbiota, physical exercise and metabolic diseases was performed. Eight clinical studies met the inclusion criteria, six in subjects with obesity and two in individuals with T2DM. In three studies carried out in individuals with obesity, exercise was able to positively modulate the diversity of GM and the abundance of some species of bacteria, mostly by increasing the Bifidobacteriaceae family, and the Bacteroides and Akkermansia genera, and by decreasing the Proteobacteria phylum. The studies in subjects with T2DM found that physical exercise may reduce metabolic endotoxemia markers.ConclusionsPhysical exercise may be a beneficial modulation strategy of GM composition in metabolic diseases, specifically aerobic exercises carried out for at least 6 weeks with moderate or high intensity. Nevertheless, well-designed clinical trials are needed to clarify the role of physical exercise on GM in subjects with obesity and T2DM.     

Apelin secretion and expression of apelin receptors in 3T3-L1 adipocytes are differentially regulated by angiotensin type 1 and type 2 receptors

Adipocytes play pivotal roles in regulating metabolism through secretion of a variety of adipokines, which in turn is regulated by other metabolic factors (e.g., insulin). Understanding the regulations of adipokine secretion is important because adipokines are implicated with metabolic disorders, such as, obesity and diabetes mellitus. Here, we investigated the regulatory roles of angiotensin II (AngII) on the secretion of apelin in 3T3-L1 adipocytes, and distinct signaling pathways mediated by AngII receptor type 1 (AT₁) and type 2 (AT₂) were revealed. It was found that activation of AT₁ receptors stimulates apelin secretion in Ca²⁺, protein kinase C, and MAPK kinase dependent ways while activation of AT₂ receptors inhibits apelin secretion through cAMP and cGMP dependent pathways. Furthermore, we demonstrate that the expression of apelin receptor (APJ) is also similarly regulated by AT₁ and AT₂ receptors. Finally, a detailed AngII signaling map is proposed.     

Natriuretic peptides in the control of lipid metabolism and insulin sensitivity

Natriuretic peptides have long been known for their cardiovascular function. However, a growing body of evidence emphasizes the role of natriuretic peptides in human substrate and energy metabolism, thereby connecting the heart with several insulin‐sensitive organs like adipose tissue, skeletal muscle and liver. Obesity may be associated with an impaired regulation of the natriuretic peptide system, also indicated as a natriuretic handicap. Evidence points towards a contribution of this natriuretic handicap to the development of obesity, type 2 diabetes mellitus and cardiometabolic complications, although the causal relationship is not fully understood. Nevertheless, targeting the natriuretic peptide pathway may improve metabolic health in obesity and type 2 diabetes mellitus. This review will focus on current literature regarding the metabolic roles of natriuretic peptides with emphasis on lipid metabolism and insulin sensitivity. Furthermore, it will be discussed how exercise and lifestyle intervention may modulate the natriuretic peptide‐related metabolic effects.     

Perfil metabólico-inflamatorio en la transición obesidad,síndrome metabólico y diabetes mellitus en población mediterránea. Estudio DARIOS Inflamatorio

Introduction and objectivesThere is a paucity of data regarding the differences in the biomarker profiles of patients with obesity, metabolic syndrome, and diabetes mellitus as compared to a healthy, normal weight population. We aimed to study the biomarker profile of the metabolic risk continuum defined by the transition from normal weight to obesity, metabolic syndrome, and diabetes mellitus.MethodsWe performed a pooled analysis of data from 7 cross-sectional Spanish population-based surveys. An extensive panel comprising 20 biomarkers related to carbohydrate metabolism, lipids, inflammation, coagulation, oxidation, hemodynamics, and myocardial damage was analyzed. We employed age- and sex-adjusted multinomial logistic regression models for the identification of those biomarkers associated with the metabolic risk continuum phenotypes: obesity, metabolic syndrome, and diabetes mellitus.ResultsA total of 2851 subjects were included for analyses. The mean age was 57.4 (8.8) years, 1269 were men (44.5%), and 464 participants were obese, 443 had metabolic syndrome, 473 had diabetes mellitus, and 1471 had a normal weight (healthy individuals). High-sensitivity C-reactive protein, apolipoprotein B100, leptin, and insulin were positively associated with at least one of the phenotypes of interest. Apolipoprotein A1 and adiponectin were negatively associated.ConclusionsThere are differences between the population with normal weight and that having metabolic syndrome or diabetes with respect to certain biomarkers related to the metabolic, inflammatory, and lipid profiles. The results of this study support the relevance of these mechanisms in the metabolic risk continuum. When metabolic syndrome and diabetes mellitus are compared, these differences are less marked.Full English text available from: www.revespcardiol.org/en     

Insulin resistance--a common link between type 2 diabetes and cardiovascular disease

Evidence suggests that diabetes and cardiovascular disease (CVD) may share an underlying cause(s), a theory known as the 'common soil' hypothesis. Insulin resistance is central both to the progression from normal glucose tolerance to type 2 diabetes and to a constellation of cardiovascular risk factors known as the metabolic syndrome. These risk factors include visceral obesity and dyslipidaemia characterized by low levels of high-density lipoprotein cholesterol, hypertriglyceridaemia and raised small dense low-density lipoprotein particle levels. Changes in adipose tissue mass and metabolism may link insulin resistance and visceral obesity, a condition that is common in type 2 diabetes. Furthermore, weight reduction, increased physical activity, metformin and acarbose have been shown to reduce the development of type 2 diabetes in genetically predisposed subjects and may decrease the high cardiovascular risk of patients with diabetes. Some fatty acid derivatives can affect energy metabolism by activating peroxisome proliferator-activated receptors (PPARs), nuclear receptors that play a key role in energy homeostasis. These receptors represent an ideal therapeutic target for reducing cardiovascular risk, because they are involved in the regulation of both insulin action and lipid metabolism. In addition to lifestyle changes, PPARgamma agonists such as thiazolidinediones are frequently beneficial and have been shown to ameliorate insulin resistance, while activation of PPARalpha (e.g. by fibrates) can lead to improvements in free fatty acid oxidation and lipid profile, and a reduction in cardiovascular events. The development of agents with both PPARalpha and PPARgamma activity promises added benefits with amelioration of insulin resistance, delayed progression to and of type 2 diabetes and a reduction of CVD.     

Activation of the STING-IRF3 pathway promotes hepatocyte inflammation,apoptosis and induces metabolic disorders in nonalcoholic fatty liver disease

BackgroundNonalcoholic fatty liver disease (NAFLD) is a common result of obesity and metabolic syndrome. Hepatocyte injury and metabolic disorders are hallmarks of NAFLD. Stimulator of interferon genes (STING) and its downstream factor interferon regulatory factor 3 (IRF3) trigger inflammatory reaction in response to the presence of cytosolic DNA. STING has recently been shown to play an important role in early alcoholic liver disease. However, little is known about the role of STING-IRF3 pathway in hepatocyte injury. Here, we aimed to examine the effect of STING-IRF3 pathway on hepatocyte metabolism, inflammation and apoptosis.MethodsWe examined the activation of the STING-IRF3 pathway, a high-fat diet (HFD)-induced obese mouse model, and determined the role of this pathway in a free fatty acid (FFA)-induced hepatocyte inflammatory response, injury, and dysfunction in L-O2 human liver cells.ResultsSTING and IRF3 were upregulated in livers of HFD-fed mice and in FFA-induced L-O2 cells. Knocking down either STING or IRF3 led to a significant reduction in FFA-induced hepatic inflammation and apoptosis, as evidenced by modulation of the nuclear factor κB (NF-κB) signaling pathway, inflammatory cytokines, and apoptotic signaling. Additionally, STING/IRF3 knockdown enhanced glycogen storage and alleviated lipid accumulation, which were found to be associated with increased expression of hepatic enzymes in glycolysis and lipid catabolism, and attenuated expression of hepatic enzymes in gluconeogenesis and lipid synthesis.ConclusionsOur results suggest that the STING-IRF3 pathway promotes hepatocyte injury and dysfunction by inducing inflammation and apoptosis and by disturbing glucose and lipid metabolism. This pathway may be a novel therapeutic target for preventing NAFLD development and progression.     

The beta-1 adrenergic antagonist, atenolol, decreases acylation stimulating protein, exercise capacity and plasma free fatty acids in men with type 2 diabetes

Background and aimsAtenolol is a beta-1 adrenergic antagonist commonly prescribed for the treatment of systemic hypertension or coronary artery disease yet its use in individuals with type 2 diabetes mellitus (T2DM) is controversial due to potentially negative side effects on insulin resistance. Non-esterified fatty acid (NEFA) metabolism is altered in T2DM especially under conditions of metabolic stress such as exercise or the postprandial state. We evaluated atenolol effects on circulating NEFA and related hormones in men with T2DM during acute cardiorespiratory exercise in both the fasting and postprandial state, including the adipokine acylation stimulating protein (ASP) which stimulates adipose tissue NEFA uptake.Methods and resultsTen men with T2DM underwent four 1-h exercise sessions at 60% of their maximal oxygen uptake (VO_2max) under the following conditions: 1) fasting (F), and 2) 2 h postprandial (PP) without medication; and 3) fasting (F-Atenolol), and 4) 2 h postprandial (PP-Atenolol) after a one-week treatment with atenolol. Results were tested for the effects of atenolol via two-way ANOVA for the F vs F-Atenolol and PP vs PP-Atenolol states separately. Atenolol treatment decreased fasting and postprandial glycerol (p < 0.0001) and NEFA (p < 0.0001), postprandial epinephrine (p = 0.048), postprandial cortisol (p = 0.02), postprandial ASP (p = 0.04) and postprandial dopamine (p < 0.004).ConclusionAtenolol alters fatty acid metabolism and associated metabolic hormones including ASP during exercise in men with T2DM and its effects are more apparent during conditions of stress such as the postprandial state, acute exercise and obesity.     

The link between abdominal obesity, metabolic syndrome and cardiovascular disease

AimThe prevalence of metabolic syndrome has increased dramatically in recent years, and the cluster of metabolic abnormalities it encompasses results in increased cardiovascular morbidity and mortality. The role of abdominal (visceral) obesity and the underlying molecular and cellular mechanisms central to this association have been the subject of intensive research in recent times. The aim of this review is to correlate data in this area, highlighting the central role of excess visceral fat and its secreted adipokines, and to review existing and emerging therapies.Data synthesisData were generated from a search of the PubMed database using the terms ‘abdominal obesity’, ‘metabolic syndrome’, ‘insulin resistance’, ‘adipokines’, ‘interleukin-6 (IL-6)’, ‘adiponectin’, ‘tumour necrosis factor-alpha (TNF-α)’ and ‘cardiovascular disease’.ConclusionMetabolic syndrome is associated with a pro-inflammatory state, and the role of visceral obesity is thought to be central to this. Visceral obesity leads to alteration of the normal physiological balance of adipokines, insulin resistance, endothelial dysfunction and a pro-atherogenic state. In association with this, the presence of conventional cardiovascular risk factors such as hypertension, dyslipidaemia and smoking results in a significantly elevated cardiovascular and metabolic (cardiometabolic) risk. Better understanding of the molecular mechanisms central to this association has led to the development of potential therapeutic agents.     

Physiology and pathophysiology of liver lipid metabolism

Liver lipid metabolism and its modulation are involved in many pathologic conditions, such as obesity, non-alcoholic fatty liver disease, diabetes mellitus, atherosclerosis and cardiovascular disease. Metabolic disorders seem to share a similar background of low-grade chronic inflammation, even if the pathophysiological mechanisms leading to tissue and organ damage have not been completely clarified yet. The accumulation of neutral lipids in the liver is now recognized as a beneficial and protective mechanism; on the other hand, lipoperoxidation is involved in the development and progression of non-alcoholic steatohepatitis. The role of the gut microbiota in liver lipid metabolism has been the object of recent scientific investigations. It is likely that the gut microbiota is involved in a complex metabolic modulation and the translocation of gut microflora may also contribute to maintaining the low-grade inflammatory status of metabolic syndrome. Therefore, lipid metabolism pathology has vague limits and complex mechanisms, and the knowledge of these is essential to guide diagnostic and therapeutic decisions.     

Regulation of skeletal muscle sucrose, non-fermenting 1/AMP-activated protein kinase-related kinase (SNARK) by metabolic stress and diabetes

Aims/hypothesis  

Sucrose, non-fermenting 1/AMP-activated protein kinase-related kinase (SNARK) is involved in cellular stress responses linked to obesity and type 2 diabetes. We determined the role of SNARK in response to metabolic stress and insulin action on glucose and lipid metabolism in skeletal muscle.     

Modulation of fatty acid metabolism as a potential approach to the treatment of obesity and the metabolic syndrome

Increased de novo lipogenesis and reduced fatty acid oxidation are probable contributors to adipose accretion in obesity. Moreover, these perturbations have a role in leading to non-alcoholic steatohepatitis, dyslipidemia, and insulin resistance—via “lipotoxicity”-related mechanisms. Research in this area has prompted an effort to evaluated several discrete enzymes in these pathways as targets for future therapeutic intervention. Acetyl-CoA carboxylase 1 (ACC1) and ACC2 regulate fatty acid synthesis and indirectly control fatty acid oxidation via a key product, malonyl CoA. Based on mouse genetic and preclinical pharmacologic evidence, inhibition of ACC1 and/or ACC2 may be a useful approach to treat obesity and metabolic syndrome. Similarly, available data suggest that inhibition of other enzymes in this pathway, including fatty acid synthase, stearoyl CoA desaturase, and diacylglycerol acytransferase 1, will have beneficial effects. AMP-activated protein kinase is a master regulator of nutrient metabolism, which controls several aspects of lipid metabolism. Activation of AMPK in selected tissues is also a potential therapeutic approach. Inhibition of hormonesensitive lipase is another possible approach. The rationale for modulating the activity of these enzymes and their relative merits (and downsides) as possible therapeutic targets are further discussed.     

Review: Peroxisome proliferator-activated receptor gamma and adipose tissue--understanding obesity-related changes in regulation of lipid and glucose metabolism

CONTEXT: Adipose tissue is a metabolically dynamic organ, serving as a buffer to control fatty acid flux and a regulator of endocrine function. In obese subjects, and those with type 2 diabetes or the metabolic syndrome, adipose tissue function is altered (i.e. adipocytes display morphological differences alongside aberrant endocrine and metabolic function and low-grade inflammation). EVIDENCE ACQUISITION: Articles on the role of peroxisome proliferator-activated receptor gamma (PPARgamma) in adipose tissue of healthy individuals and those with obesity, metabolic syndrome, or type 2 diabetes were sourced using MEDLINE (1990-2006). EVIDENCE SYNTHESIS: Articles were assessed to provide a comprehensive overview of how PPARgamma-activating ligands improve adipose tissue function, and how this links to improvements in insulin resistance and the progression to type 2 diabetes and atherosclerosis. CONCLUSIONS: PPARgamma is highly expressed in adipose tissue, where its activation with thiazolidinediones alters fat topography and adipocyte phenotype and up-regulates genes involved in fatty acid metabolism and triglyceride storage. Furthermore, PPARgamma activation is associated with potentially beneficial effects on the expression and secretion of a range of factors, including adiponectin, resistin, IL-6, TNFalpha, plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and angiotensinogen, as well as a reduction in plasma nonesterified fatty acid supply. The effects of PPARgamma also extend to macrophages, where they suppress production of inflammatory mediators. As such, PPARgamma activation appears to have a beneficial effect on the relationship between the macrophage and adipocyte that is distorted in obesity. Thus, PPARgamma-activating ligands improve adipose tissue function and may have a role in preventing progression of insulin resistance to diabetes and endothelial dysfunction to atherosclerosis.     

Evaluation of ADL and BMI in the management of diabetes mellitus at secondary and tertiary health facilities

AimsPhysical activities of daily living (ADL) constitutes one of diabetes management options. This study aimed to assess the extent that ADL and BMI are evaluated among diabetes patients in hospital practice.MethodThis was a clinical observational baseline study in two hospitals. Audit of medical files was performed to assess if BMI and occupations were recorded (N = 112). Afterwards, ‘N = 38’ who consented to participate in prospective study were conveniently sampled to assess ADL in relation to accessible metabolic syndrome tests. A validated questionnaire was used to collect data, which were analysed using SPSS version 20.ResultsAudit shows 55/112 of clients’ occupation were taken, of which 31% has BMI record. Those with lipid profile results are without blood pressure and vice versa. In the cross-sectional assessment, 74% are in physically demanding ADL occupations, but affirmed inactivity is 98% on leisure exercise. Further, 47% have BMI >25 kg/m² and were consistently less active on all leisure ADL relative to those with BMI <25 kg/m² (p < 0.02).ConclusionThis report highlights oversight in clinical practice, whereby accessible metabolic syndrome parameters and occupation of clients living with diabetes are being assessed inconsistently. This implies an unmet need in the integration BMI and occupational information to improve diabetes self-management.     

过氧化物酶体增殖物活化受体γ与糖脂代谢

过氧化物酶体增殖物活化受体(PPAR)属于核受体超家族一员,与其他甾体类激素受体一样,也是配体激活的转录因子.2型糖尿病与肥胖等代谢性疾病严重影响人类的健康,噻唑烷二酮类(TZDs)药物作为PPAR的激动剂,在脂肪细胞分化、糖脂代谢、胰岛素抵抗中起重要作用.PPAR的常见基因多态性与2型糖尿病、肥胖、脂代谢异常等有关,现仅就PPARγ与糖脂代谢的关系综述如下.