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An imbalance between caloric intake and energy expenditure leads to obesity. Obesity is an important risk factor for the development of several metabolic diseases including insulin resistance, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. So, controlling obesity could be effective in the improvement of obesity-related diseases. Various factors are involved in obesity, such as AMP-activated protein kinases (AMPK), silent information regulators, inflammatory mediators, oxidative stress parameters, gastrointestinal hormones, adipokines, angiopoietin-like proteins, and microRNAs. These factors play an important role in obesity by controlling fat metabolism, energy homeostasis, food intake, and insulin sensitivity. AMPK is a heterotrimeric serine/threonine protein kinase known as a fuel-sensing enzyme. The central role of AMPK in obesity makes it an attractive molecule to target obesity and related metabolic diseases. In this review, the critical role of AMPK in obesity and the interplay between AMPK and obesity-associated factors were elaborated.  相似文献   

3.
Over the past two decades increases in obesity, due to high caloric intakes and immobilizing technologies, has led to a surge in type 2 diabetes. In obesity elevated circulating fatty acids set-off a pro-inflammatory cascade that increases the production of tumour necrosis factor-α (TNFα) from macrophages. Obesity is associated with blunted skeletal muscle fatty acid oxidation, accumulation of bioactive lipids and insulin resistance. The factors contributing to defects in fatty acid metabolism are not understood but new data demonstrates that increased TNFα in obesity increases protein phosphatase 2C (PP2C), which in turn suppresses the activity of AMP-activated protein kinase (AMPK), a critical regulator of energy metabolism 1. These data identify a novel mechanism by which inflammation in obesity is a precursor to defects in skeletal muscle fatty acid oxidation that generates a vicious cycle exacerbating the development of insulin resistance.  相似文献   

4.
Genetic aspects of susceptibility to obesity and related dyslipidemias   总被引:4,自引:0,他引:4  
Obesity has a multifactorial origin. However, although environmental variables undoubtedly play a role in the development of obesity, it is now clear that genetic variation is also involved in the determination of an individual's susceptibility to body fat accumulation. In addition, it is also widely accepted that obesity is not a single homogeneous phenotype. It is also heterogeneous regarding its causes and metabolic complications. The regional distribution of body fat appears to be an important correlate of the metabolic complications that have been related to obesity. Due to their higher accumulation of abdominal fat, men are generally more at risk for the metabolic complications of obesity than women whereas some obese women, with large gluteal-femoral adipose depots may have a cosmetic problem which may not necessarily require medical intervention. Several studies have been conducted to understand the mechanisms by which abdominal obesity is related to diabetes, hypertension and cardiovascular disease. It appears that the increased risk of abdominal obesity is the result of complex hormonal and metabolic interactions. Studies in genetic epidemiology have shown that both total body fatness and the regional distribution of body fat have a significant genetic component. Standardized intervention studies using an identical twin design have shown that individuals that have the same genetic background tend to show similar changes in body fat and in plasma lipoprotein levels when exposed to standardized caloric excess or energy restriction. Finally, although abdominal obesity is a significant risk factor for cardiovascular disease, not every abdominal obese subject will experience metabolic complications, suggesting that some obese individuals may be more susceptible than others. Variation in several genes relevant to lipid and lipoprotein metabolism may alter the relation of abdominal obesity to dyslipoproteinemias. Abdominal obesity should therefore be considered as a factor that exacerbates an individual's susceptibility to cardiovascular disease.  相似文献   

5.
To investigate the contributions of two surgical gut manipulations—exclusion of the proximal intestine from alimentary flow and exposure of the jejunum to partially digested nutrients—to body weight regulation and metabolism, we have developed a rat model of an investigational device, the endoluminal sleeve (ELS). The ELS is a 10 cm, nutrient‐impermeable, flexible tube designed for endoluminal implantation. ELS devices were surgically implanted in the duodenal bulb of rats with diet‐induced obesity. Body weight, food intake, stool caloric content, and glucose homeostasis were subsequently evaluated. ELS‐implanted rats demonstrated a 20% reduction of body weight compared to sham‐operated (SO) controls. ELS‐treated animals consumed an average of 27% fewer kcal/day than SO, and there was no evidence of malabsorption. ELS treatment improved fasting glycemia and glucose tolerance after oral and intraperitoneal (IP) administration. ELS treatment enhanced insulin sensitivity, as demonstrated by decreased fasting and glucose‐stimulated insulin levels and confirmed by calculation of homeostasis model assessment of insulin resistance (IR). These data suggest that selective bypass of the proximal intestine by ELS, with enhanced delivery of partially digested nutrients to the jejunum, mimics many of the effects of Roux‐en‐Y gastric bypass (RYGB) on body weight and glucose metabolism. Thus, ELS implantation may be an effective treatment for obesity and diabetes. Since the ELS device is amenable to endoscopic placement, it may offer a valuable alternative to more invasive surgical approaches in selected patients with obesity and its metabolic complications.  相似文献   

6.
Obesity is a global health issue, as it is associated with increased risk of developing chronic conditions associated with disorders of metabolism such as type 2 diabetes and cardiovascular disease. A better understanding of how excessive fat accumulation develops and causes diseases of the metabolic syndrome is urgently needed. The hypothalamic melanocortin system is an important point of convergence connecting signals of metabolic status with the neural circuitry that governs appetite and the autonomic and neuroendocrine system controling metabolism. This system has a critical role in the defense of body weight and maintenance of homeostasis. Two neural melanocortin receptors, melanocortin 3 and 4 receptors (MC3R and MC4R), play crucial roles in the regulation of energy balance. Mutations in the MC4R gene are the most common cause of monogenic obesity in humans, and a large literature indicates a role in regulating both energy intake through the control of satiety and energy expenditure. In contrast, MC3Rs have a more subtle role in energy homeostasis. Results from our lab indicate an important role for MC3Rs in synchronizing rhythms in foraging behavior with caloric cues and maintaining metabolic homeostasis during periods of nutrient scarcity. However, while deletion of the Mc3r gene in mice alters nutrient partitioning to favor accumulation of fat mass no obvious role for MC3R haploinsufficiency in human obesity has been reported. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.  相似文献   

7.
The superoxide dismutase mimetic manganese [III] tetrakis [5,10,15,20]-benzoic acid porphyrin (MnTBAP) is a potent antioxidant compound that has been shown to limit weight gain during short-term high fat feeding without preventing insulin resistance. However, whether MnTBAP has therapeutic potential to treat pre-existing obesity and insulin resistance remains unknown. To investigate this, mice were treated with MnTBAP or vehicle during the last five weeks of a 24-week high fat diet (HFD) regimen. MnTBAP treatment significantly decreased body weight and reduced white adipose tissue (WAT) mass in mice fed a HFD and a low fat diet (LFD). The reduction in adiposity was associated with decreased caloric intake without significantly altering energy expenditure, indicating that MnTBAP decreases adiposity in part by modulating energy balance. MnTBAP treatment also improved insulin action in HFD-fed mice, a physiologic response that was associated with increased protein kinase B (PKB) phosphorylation and expression in muscle and WAT. Since MnTBAP is a metalloporphyrin molecule, we hypothesized that its ability to promote weight loss and improve insulin sensitivity was regulated by heme oxygenase-1 (HO-1), in a similar fashion as cobalt protoporphyrins. Despite MnTBAP treatment increasing HO-1 expression, administration of the potent HO-1 inhibitor tin mesoporphyrin (SnMP) did not block the ability of MnTBAP to alter caloric intake, adiposity, or insulin action, suggesting that MnTBAP influences these metabolic processes independent of HO-1. These data demonstrate that MnTBAP can ameliorate pre-existing obesity and improve insulin action by reducing caloric intake and increasing PKB phosphorylation and expression.  相似文献   

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Brain circuits regulating energy homeostasis   总被引:2,自引:0,他引:2  
Recent years have seen an impetus in the study for central mechanisms regulating energy balance, and caloric intake possibly as a response to the obesity pandemic. This renewed interest as well as drastic improvements in the tools that are now currently available to neuroscientists, has yielded a great deal of insight into the mechanisms by which the brain regulates metabolic function, and volitional aspects of feeding in response to metabolic signals like leptin, insulin and ghrelin. Among these mechanisms are the complex intracellular signals elicited by these hormones in neurons. Moreover, these signals produce and modulate the metabolism of the cell at the level of the mitochondria. Finally, these signals promote plastic changes that alter the synaptic circuitry in a number of circuits and ultimately affect cellular, physiological and behavioral responses in defense of energy homeostasis. These mechanisms are surveyed in this review.  相似文献   

10.
Obesity is widely recognized as a major global health problem caused by a chronic energy imbalance resulting from a combination of excess caloric intake and insufficient energy expenditure. Excessive energy intake and physical inactivity are traditional risk factors for obesity. Obesity is a risk factor for many diseases, including hypertension, diabetes and tumours. Recent studies have found a strong link between ferroptosis and obesity. Ferroptosis is an iron-dependent regulated cell death caused by iron overload and reactive oxygen species-dependent excessive accumulation of lipid peroxidation. Ferroptosis is involved in many biological processes, such as amino acid metabolism, iron metabolism and lipid metabolism. Some potential strategies to reduce the adverse effects of ferroptosis on obesity are suggested and future research priorities are highlighted.  相似文献   

11.
《Endocrine practice》2021,27(10):1056-1061
ObjectiveNonnutritive (NNSs) are used in place of sugars to reduce caloric and glycemic intake while providing desired sweetness, commonly replacing sugar-sweetened beverages (SSBs) with “diet” (zero-calorie) alternatives. Concern has developed due to observational data associating NNSs with obesity and adiposity-based chronic disease. This counterpoint argues that, in general, NNSs used in place of added or excess sugars in the diet are likely beneficial.MethodsA literature review was conducted on interventional trials investigating NNSs and obesity or type 2 diabetes mellitus. Key words used in the search included artificial sweeteners, nonnutritive sweeteners, saccharin, sucralose, aspartame, stevia/steviol, acesulfame potassium, meal replacements, type 2 diabetes mellitus, obesity, and weight.ResultsInterventional data and indirect interventional data consistently showed beneficial effects on weight and cardiometabolic health, including glycemia, when SSBs or other energy-dense foods were replaced by artificially sweetened beverages or artificially sweetened meal replacements.ConclusionAlthough NNSs correlate with obesity and adiposity-based chronic disease, those data are fraught with confounding and error. Plausibility has been suggested on the basis of preclinical research on neuroendocrine control of appetite, satiety, and cravings plus the gut microbiome. However, interventional data reveal that replacing caloric/glycemic energy intake via NNSs creates an energy deficit resulting in weight loss and improvement in disease—especially dysglycemic disease. Intensive dietary intervention using artificially sweetened meal replacements shows a marked clinical benefit without detriment from their NNSs. Furthermore, beverages sweetened with NNSs rather than SSBs have been noted to be a critical component for those succeeding in maintaining weight loss. Although individual responses to the effects of NNSs are always warranted just like in any clinical situation, patients should not be advised to avoid NNSs in the context of dietary intervention to improve quality and energy deficit.  相似文献   

12.
Insulin resistance, often associated with obesity, precipitates metabolic syndrome, type 2 diabetes, and finally, atherosclerosis. Sources of excess energy cause abnormal accumulation of tissue lipids leading to cellular dysfunction through cellular stress and inflammation. This process is often referred to as lipotoxicity. Until date, effective approaches that aim to overcome insulin resistance involve amelioration of obesity by caloric restriction and/or exercise. Quantitative control of lipids, especially triglycerides and fatty acids in adipose and other tissues, and plasma can be addressed using these measures. However, altering tissue lipid composition may provide another strategy to prevent or control lipotoxicity. Endogenous fatty acid synthesis plays a crucial role in determining tissue energy states. As a target gene of SREBP-1 that controls lipogenesis we identified a unique enzyme, Elovl6, which is responsible for the final step in endogenous saturated fatty acid synthesis, thereby controlling tissue fatty acid composition. Elovl6-deficient mice become obese and develop hepatosteatosis when fed a high-fat diet or when mated to leptin-deficient ob/ob mice. However, the mice exhibited marked protection from hyperinsulinemia, hyperglycemia, and hyperleptinemia. Hepatic fatty acid composition is a novel determinant of insulin sensitivity independent of cellular energy balance. Inhibiting Elovl6 activity may provide a novel therapeutic approach for treating insulin resistance, diabetes, metabolic syndrome, and cardiovascular risks by circumventing obesity problems. In this review, we consider fatty acid metabolism and lipotoxicity, and discuss the role of Elovl6 in newly recognized aspects of metabolic regulation.  相似文献   

13.
2型糖尿病是一种常见的慢性消耗性疾病,其发病机制十分复杂,流行病学研究表明,肥胖、高热量饮食、体力活动不足及年龄增大是2型糖尿病最主要的环境因素。它是一种以胰岛素抵抗和胰岛素分泌不足为特征的代谢性疾病。肠道菌群作为进入人体的一个重要环境因素,肠道微生物的菌群变化影响宿主能量物质的吸收,调节肠道的分泌功能和非特异性免疫功能,从营养、代谢、疾病等各方面与我们生命活动相关。肠道菌群已成为我们身体的一部分,影响宿主的免疫,在肥胖、糖尿病、代谢综合征等疾病中都具有非常重要的作用。  相似文献   

14.
Obesity and cardiovascular disease are among the world's leading causes of death, especially in Western countries where consumption of high caloric food is commonly accompanied by low physical activity. This lifestyle often leads to energy imbalance, obesity, diabetes and their associated metabolic disorders, including cardiovascular diseases. It has become increasingly recognized that obesity and cardiovascular disease are metabolically linked, and a better understanding of this relationship requires that we uncover the fundamental genetic mechanisms controlling obesity-related heart dysfunction, a goal that has been difficult to achieve in higher organisms with intricate metabolic complexity. However, the high degree of evolutionary conservation of genes and signalling pathways allows researchers to use lower animal models such as Drosophila, which is the simplest genetic model with a heart, to uncover the mechanistic basis of obesity-related heart disease and its likely relevance to humans. Here, we discuss recent advances made by using the power of the Drosophila as a powerful model to investigate the genetic pathways by which a high fat diet may lead to heart dysfunction.  相似文献   

15.
The increasing national prevalence of obesity is a major public health concern and a substantial burden on the health care resources of Canada. In addition to the direct health impact of obesity, this condition is a well-established risk factor for the development of various prevalent comorbidities including type 2 diabetes, hypertension, and cardiovascular disease. Historically, adipose tissue has been regarded primarily as an organ for energy storage. However, the discovery of leptin in the mid 1990's revolutionized our understanding of this tissue and has focused attention on the endocrine function of adipose tissue as a source of secreted bioactive peptides. These compounds, collectively termed adipokines, regulate a number of biological functions including appetite and energy balance, insulin sensitivity, lipid metabolism, blood pressure, and inflammation. The physiological importance of adipokines has led to the hypothesis that changes in the synthesis and secretion of these compounds in the obese are a causative factor contributing to the development of obesity and obesity-related diseases in these individuals. Following from this it has been proposed that pharmacologic manipulation of adipokine levels may provide novel effective therapeutic strategies to treat and prevent obesity, type 2 diabetes, and cardiovascular disease.  相似文献   

16.
The role of PAS kinase in regulating energy metabolism   总被引:1,自引:0,他引:1  
Hao HX  Rutter J 《IUBMB life》2008,60(4):204-209
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17.
The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis.  相似文献   

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Animal models for insulin resistance and type 2 diabetes are required for the study of the mechanism of these phenomena and for a better understanding of diabetes complications in human populations. Type 2 diabetes is a syndrome that affects 5-10% of the adult population. Hyperinsulinaemia, hypertriglyceridaemia, decreased high-density lipoprotein (HDL) cholesterol levels, obesity and hypertension, all form a cluster of risk factors that increase the risk of coronary artery disease, and are known as insulin resistance syndrome or syndrome X. The gerbil, Psammomys obesus is characterized by primary insulin resistance and is a well-defined model for dietary induced type 2 diabetes. Weanling Psammomys and Albino rats were held individually for several weeks on high energy (HE) and low energy (LE) diets in order to determine the development of metabolic changes leading to diabetes. Feeding Psammomys on HE diet resulted in hyperglycaemia (303 +/- 40 mg/dl), hyperinsulinaemia (194 +/- 31 microU/ml) and a moderate elevation in body weight, obesity and plasma triglycerides. Albino rats on HE diet demonstrated an elevation in plasma insulin (30 +/- 4 microU/ml), hypertriglyceridaemia (170 +/- 11 mg/dl), an elevation in body weight and obesity, but maintained normoglycaemia (98 +/- 6 mg/dl). Psammomys represent a model that is similar to human populations, with primary insulin resistance expressed in young age, which leads to a high percentage of adult type 2 diabetes. Examples for such populations are the Pima Indians, Australian Aborigines and many other Third World populations. The results indicate that the metabolism of Psammomys is well adapted towards life in a low energy environment, where Psammomys takes advantage of its capacity for a constant accumulation of adipose tissue that will serve for maintenance and breeding in periods of scarcity. This metabolism known as 'thrifty metabolism', is compromised at a high nutrient intake.  相似文献   

20.
The hormones insulin and leptin have been proposed to act in the central nervous system (CNS) as adiposity signals as part of a theoretical negative feedback loop that senses the caloric stores of an animal and orchestrates adjustments in energy balance and food intake. Much research has provided support for both the existence of such a feedback loop and the specific roles that insulin and leptin may play. Most studies have focused on hypothalamic sites, which historically are implicated in the regulation of energy balance, and on the brain stem, which is a target for neural and humoral signals relating to ingestive acts. More recent lines of research, including studies from our lab, suggest that in addition to these CNS sites, brain reward circuitry may be a target for insulin and leptin action. These studies are reviewed together here with the goals of providing a historical overview of the findings that have substantiated the originally hypothesized negative feedback model and of opening up new lines of investigation that will build on these findings and allow further refinement of the model of adiposity signal/CNS feedback loop. The understanding of how motivational circuitry and its endocrine or neuroendocrine modulation contributes to normal energy balance regulation should expand possibilities for future therapeutic approaches to obesity and may lead to important insights into mental illnesses such as substance abuse or eating disorders.  相似文献   

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