肥胖相关代谢性炎症研究进展

肥胖是能量代谢失衡所导致的体脂过度积聚,可引起动脉粥样硬化、胰岛素抵抗和血脂异常等多种代谢综合征的发生。肥胖本身是一种发生在脂肪组织的慢性炎症疾病,伴随着脂肪组织细胞内炎症信号通路的激活、炎性细胞因子的释放和免疫细胞的浸润等病理改变。脂肪组织释放的炎症介质也可以进入循环系统而影响其他器官组织功能,引起相关代谢综合征的发生。因此,研究代谢性炎症与肥胖的关系对肥胖及其相关代谢性疾病的防治具有深远意义,针对肥胖代谢炎症的治疗方法也将为肥胖及其相关代谢疾病的治疗带来新的思路。     

Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ.

The traditional role attributed to white adipose tissue is energy storage, fatty acids being released when fuel is required. The metabolic role of white fat is, however, complex. For example, the tissue is needed for normal glucose homeostasis and a role in inflammatory processes has been proposed. A radical change in perspective followed the discovery of leptin; this critical hormone in energy balance is produced principally by white fat, giving the tissue an endocrine function. Leptin is one of a number of proteins secreted from white adipocytes, which include angiotensinogen, adipsin, acylation-stimulating protein, adiponectin, retinol-binding protein, tumour neorosis factor a, interleukin 6, plasminogen activator inhibitor-1 and tissue factor. Some of these proteins are inflammatory cytokines, some play a role in lipid metabolism, while others are involved in vascular haemostasis or the complement system. The effects of specific proteins maybe autocrine or paracrine, or the site of action maybe distant from adipose tissue. The most recently described adipocyte secretory proteins are fasting-induced adipose factor, a fibrinogen-angiopoietin-related protein, metallothionein and resistin. Resistin is an adipose tissue-specific factor which is reported to induce insulin resistance, linking diabetes to obesity. Metallothionein is a metal-binding and stress-response protein which may have an antioxidant role. The key challenges in establishing the secretory functions of white fat are to identify the complement of secreted proteins, to establish the role of each secreted protein, and to assess the pathophysiological consequences of changes in adipocyte protein production with alterations in adiposity (obesity, fasting, cachexia). There is already considerable evidence of links between increased production of some adipocyte factors and the metabolic and cardiovascular complications of obesity. In essence, white adipose tissue is a major secretory and endocrine organ involved in a range of functions beyond simple fat storage.     

Self-selected macronutrient diet affects energy and glucose metabolism in brown fat-ablated mice

OBJECTIVE: Obese transgenic UCP-DTA mice have largely ablated brown adipose tissue and develop obesity and diabetes, which are highly susceptible to a high-fat diet. We investigated macronutrient self-selection and its effect on development of obesity, diabetes, and energy homeostasis in UCP-DTA mice. RESEARCH METHODS AND PROCEDURES: UCP-DTA and wild-type littermates were fed a semisynthetic macronutrient choice diet (CD) ad libitum from weaning until 17 weeks. Energy homeostasis was assessed by measurement of food intake, food digestibility, body composition, and energy expenditure. Diabetes was assessed by blood glucose measurements and insulin tolerance test. RESULTS: Wild-type and UCP-DTA mice showed a high fat preference and increased energy digestion on CD compared with a low-fat standard diet. On CD, wild-type mice accumulated less body fat (16.9%) than UCP-DTA (32.6%) mice, although they had a higher overall energy intake. Compared with wild-type mice, resting metabolic rate was reduced in UCP-DTA mice irrespective of diet. UCP-DTA mice progressively decreased their carbohydrate intake, resulting in an almost complete avoidance of carbohydrate. UCP-DTA mice developed severe insulin resistance but showed decreased fed and fasted blood glucose on CD. DISCUSSION: In contrast to wild-type mice, UCP-DTA mice were not able to reduce their weight gain efficiency on CD. This suggests that, because of the high fat preference of the background strain and the increased metabolic efficiency, brown adipose tissue-deficient mice still develop obesity and insulin resistance on a macronutrient CD even when decreasing overall energy intake. Through the avoidance of carbohydrates, however, they are able to maintain normoglycemia.     

Adipose tissue and the insulin resistance syndrome.

Obesity is associated with insulin resistance. Insulin resistance underlies a constellation of adverse metabolic and physiological changes (the insulin resistance syndrome) which is a strong risk factor for development of type 2 diabetes and CHD. The present article discusses how accumulation of triacylglycerol in adipocytes can lead to deterioration of the responsiveness of glucose metabolism in other tissues. Lipodystrophy, lack of adipose tissue, is also associated with insulin resistance. Any plausible explanation for the link between excess adipose tissue and insulin resistance needs to be able to account for this observation. Adipose tissue in obesity becomes refractory to suppression of fat mobilization by insulin, and also to the normal acute stimulatory effect of insulin on activation of lipoprotein lipase (involved in fat storage). The net effect is as though adipocytes are 'full up' and resisting further fat storage. Thus, in the postprandial period especially, there is an excess flux of circulating lipid metabolites that would normally have been 'absorbed' by adipose tissue. This situation leads to fat deposition in other tissues. Accumulation of triacylglycerol in skeletal muscles and in liver is associated with insulin resistance. In lipodystrophy there is insufficient adipose tissue to absorb the postprandial influx of fatty acids, so these fatty acids will again be directed to other tissues. This view of the link between adipose tissue and insulin resistance emphasises the important role of adipose tissue in 'buffering' the daily influx of dietary fat entering the circulation and preventing excessive exposure of other tissues to this influx.     

Adiponectin, the missing link in insulin resistance and obesity

Obesity and insulin resistance have been recognised as leading causes of major health issues, particularly diabetes type 2 and metabolic syndrome. Although obesity, defined as excess body fat, is frequently accompanied by insulin resistance, diabetes, metabolic syndrome and cardiovascular diseases, the molecular basis for the link between obesity and those diseases has not yet been clarified. Adipose tissue expresses various secretory proteins, including leptin, tumour necrosis factor-alpha and adiponectin, which may be involved in the regulation of energy expenditure, lipid metabolism and insulin resistance. The aim of this study is to provide an overview of the metabolic alterations occurring in insulin resistance as well as to review the biological roles of adiponectin, particularly in the regulation of fatty acid oxidation and insulin action. Adiponectin is the most abundant gene product in adipose tissue and accounts for 0.01% of total plasma protein. Plasma adiponectin level is decreased in obesity, both in children and adults, and it is negatively associated to plasma insulin and positively associated to plasma triglycerides. Low levels of adiponectin decreases fatty acid oxidation in muscle. Recent data have demonstrated that adiponectin effects are mediated by the interaction with muscle and hepatic receptors through activation of AMP kinase, the cellular "fuel gauge", which in turn inhibits acetyl CoA carboxylase and increases fatty acid beta-oxidation. Since there is no available recombinant adiponectin for human use, its direct effects on human metabolism remain unknown, but this hormone appears to be promising in the treatment of obesity an related metabolic disorders.     

Very-low-carbohydrate diets and preservation of muscle mass

Although the ability to make triglycerides is essential for normal physiology, excess accumulation of triglycerides results in obesity and is associated with insulin resistance. Inhibition of triglyceride synthesis, therefore, may represent a feasible strategy for the treatment of obesity and type 2 diabetes. Acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) is one of two DGAT enzymes that catalyze the final reaction in the known pathways of mammalian triglyceride synthesis. Mice lacking DGAT1 have increased energy expenditure and insulin sensitivity and are protected against diet-induced obesity and glucose intolerance. These metabolic effects of DGAT1 deficiency result in part from the altered secretion of adipocyte-derived factors. Studies of DGAT1-deficient mice have helped to provide insights into the mechanisms by which cellular lipid metabolism modulates systemic carbohydrate and insulin metabolism, and a better understanding of how DGAT1 deficiency enhances energy expenditure and insulin sensitivity may identify additional targets or strategies for the treatment of obesity and type 2 diabetes.     

Metabolic consequences of lipodystrophy in mouse models

PURPOSE OF REVIEW: Adipose tissue is a key player in metabolic homeostasis through its role as an energy depot and endocrine organ. The characterization of mouse models of lipodystrophy, in which adipose tissue development and function are impaired, has shed new light on the mechanisms by which adipose tissue dysregulation may contribute to conditions such as insulin resistance, fatty liver, and beta-cell toxicity. RECENT FINDINGS: Here we review recent findings from mouse models with genetic alterations leading to reduced adipose tissue mass. The metabolic consequences depend on the basis for the adipose tissue reduction, and we classify mouse models into three categories based on whether they confer (1) lipoatrophy accompanied by insulin resistance, (2) reduced adipose tissue storage associated with enhanced energy expenditure, or (3) both lipoatrophic and energetic effects. SUMMARY: Reductions in the capacity of adipose tissue to store triglycerides or to secrete adipokine hormones lead to altered lipid metabolism and insulin resistance. In contrast, depletion of fat stores by virtue of enhanced energy metabolism does not produce undesirable metabolic effects. However, enhanced energy metabolism cannot overcome the deleterious effects of impaired adipokine production, as revealed by studies of models with both lipoatrophic and energetic effects.     

Endocannabinoid signaling and energy metabolism: a target for dietary intervention

The endocannabinoid (EC) signaling (ECS) system involves the activation of receptors targeted by endogenously produced ligands called endocannabinoids that trigger specific physiologic events in various organs and tissues throughout the body. ECs are lipid mediators that bind to specific receptors and elicit cell signaling. The focus of this review is to discuss the responses that direct pathways of systemic energy metabolism. Recent findings have indicated that an imbalance of the ECS contributes to visceral fat accumulation and disrupts energy homeostasis, which are characteristics of the metabolic syndrome. Constant activation of ECS has been linked to metabolic processes that are associated with the hypothalamus and peripheral tissues of obese patients. In contrast, inhibition of ECS results in weight loss in animal and human subjects. Despite these findings, the mechanism involved in the dysregulation of ECS is unclear. Interestingly, the level of endogenous ligands, derived from arachidonic acid, can be directly manipulated by nutrient intervention, in that a diet rich in long-chain ω-3 polyunsaturated fatty acids will decrease the production of ligands to modulate the activation of target receptors. In contrast, a diet that is high in ω-6 polyunsaturated fatty acids will cause an increase in ECS activation and stimulate tissue specific activities that decrease insulin sensitivity in muscle and promote fat accumulation in the adipose tissue. The purpose of this review is to explain the components of ECS, its role in adipose and muscle energy metabolism, and how nutritional approaches with dietary ω-3 polyunsaturated fatty acids may reverse the dysregulation of this system to improve insulin sensitivity and control body fat.     

From obesity to diabetes

The prevalence of obesity has been increasing dramatically in the last decades in the whole world, not only in industrialized countries but also in developing areas. A major complication of obesity is insulin resistance and type 2 diabetes. Diabetes is also rapidly increasing world-wide--reaching a prevalence in adults of approx. 5-6% in Central Europe and in the US, and more than 50% in specific, genetically prone populations. This article reviews pathogenetic mechanisms linking obesity and type 2 diabetes. Emphasis is placed on the observation that excessive amounts of adipocytes are associated with an impairment of insulin sensitivity, a key feature of the "metabolic syndrome". This is a cluster of metabolic abnormalities such as type 2 diabetes, hypertension and dyslipidemia; all of them are enhanced by the presence of visceral (abdominal) obesity and all contribute to the increased cardiovascular risk observed in these patients. Besides release of free fatty acids, adipocytes secrete substances that contribute to peripheral insulin resistance, including adiponectin, resistin, TNF-alpha and interleukin 6. Increased turnover of free fatty acids interferes with intracellular metabolism of glucose in the muscle, and they exert lipotoxic effect on pancreatic beta-cells. The pre-receptor metabolism of cortisol is enhanced in visceral adipose tissue by activation of 11 beta-hydroxysteroid dehydrogenase type 1. A new class of anti-diabetic drugs (thiazolidinediones, or glitazones) bind to peroxisome proliferator activated receptor (PPAR-gamma) and lower thereby plasma free fatty acids and cytokine production in adipocytes, in addition to a decrease of resistin and an increase in adiponectin observed in animals, resulting in an overall increase in insulin sensitivity and in an improvement of glucose homeostasis. However, the first step to avoid insulin resistance and prevent the development of diabetes should be a reduction in body weight in overweight subjects, and an increase in physical activity. There are now three published randomized controlled trials demonstrating that in high risk individuals, life style changes with modest weight lost, associated with diminished fat intake and an increase in fruit and vegetable consumption result in marked inhibition of the transition from the prediabetic state to manifest type 2 diabetes.     

Effects of visceral fat accumulation in obesity and type 2 diabetes

Type 2 diabetes has become the most frequently encountered metabolic disorder in the world and obesity, meaning visceral adiposity, is the core problem. In the abdominal adipose tissue, insulin resistance (IR) reduces the antilipolytic effect of insulin, which in turn leads to reduced glucose uptake and increased release of free fatty acids (FFAs) and glycerol. Chronic exposure of beta cells to elevated FFA levels causes detrimental consequences such as increased insulin secretion at low glucose concentrations, decreased proinsulin biosynthesis, depletion of insulin reserves and reduced response to concentrations of glucose stimulus. Adipose peroxisome proliferator-activated receptors (PPAR)-γ appears to be an essential mediator for the maintenance of whole-body insulin sensitivity that protects non-adipose tissue against lipid overload. Current data suggest that PPAR-γ-activating ligands improve adipose tissue function, and may prevent the progression of IR to diabetes and also endothelial dysfunction to atherosclerosis. Links between environmental influences, the layout of visceral fat, the PPARs, the adiponectin and the adipocytokines still need to be completely clarified.     

Energy Metabolism Changes and Dysregulated Lipid Metabolism in Postmenopausal Women

Aging women experience hormonal changes, such as decreased estrogen and increased circulating androgen, due to natural or surgical menopause. These hormonal changes make postmenopausal women vulnerable to body composition changes, muscle loss, and abdominal obesity; with a sedentary lifestyle, these changes affect overall energy expenditure and basal metabolic rate. In addition, fat redistribution due to hormonal changes leads to changes in body shape. In particular, increased bone marrow-derived adipocytes due to estrogen loss contribute to increased visceral fat in postmenopausal women. Enhanced visceral fat lipolysis by adipose tissue lipoprotein lipase triggers the production of excessive free fatty acids, causing insulin resistance and metabolic diseases. Because genes involved in β-oxidation are downregulated by estradiol loss, excess free fatty acids produced by lipolysis of visceral fat cannot be used appropriately as an energy source through β-oxidation. Moreover, aged women show increased adipogenesis due to upregulated expression of genes related to fat accumulation. As a result, the catabolism of ATP production associated with β-oxidation decreases, and metabolism associated with lipid synthesis increases. This review describes the changes in energy metabolism and lipid metabolic abnormalities that are the background of weight gain in postmenopausal women.     

Is obesity-induced ECM remodeling a prelude to the development of various diseases?

Due to the increasing incidence rate of obesity worldwide and the associated complications such as type 2 diabetes and cardiovascular diseases, research on the adipose tissue physiology and the role of the extracellular matrix (ECM) has gained tremendous attention. The ECM, one of the most crucial components in body tissues, undergoes remodeling and regeneration of its constituents to guarantee normal tissue function. There is a crosstalk between fat tissue and various body organs, including but not limited to the liver, heart, kidney, skeletal muscle, and so forth. These organs respond to fat tissue signals through changes in ECM, function, and their secretory products. Obesity can cause ECM remodeling, inflammation, fibrosis, insulin resistance, and disrupted metabolism in different organs. However, the mechanisms underlying the reciprocal communication between various organs during obesity are still not fully elucidated. Gaining a profound knowledge of ECM alterations during the progression of obesity will pave the way toward developing potential strategies to either circumvent pathological conditions or open an avenue to treat complications associated with obesity.     

Obesity and type 2 diabetes

Summary  The rise in obesity – and specifically abdominal obesity – is driving the global increase in type 2 diabetes. Excess visceral fat, the causative factor behind abdominal obesity, is closely linked with β-cell dysfunction and insulin resistance, two of the key components of type 2 diabetes pathogenesis. Attempts to curb the current abdominal obesity and type 2 diabetes epidemics will require a government-led public health approach, in tandem with a personal approach aimed at helping abdominally obese individuals reduce their cardiovascular and metabolic (cardiometabolic) risk profile.     

The burden of type 2 diabetes: strategies to prevent or delay onset

Type 2 diabetes is widespread and its prevalence is increasing rapidly. In the US alone, approximately 41 million individuals have prediabetes, placing them at high risk for the development of diabetes. The pathogenesis of type 2 diabetes involves inadequate insulin secretion and resistance to the action of insulin. Suggestive data link insulin resistance and accompanying hyperglycemia to an excess of abdominal adipose tissue, a link that appears to be mediated partially by adipocyte secretion of multiple adipokines that mediate inflammation, thrombosis, atherogenesis, hypertension, and insulin resistance. The adipokine adiponectin has reduced expression in obesity and appears to be protective against the development of type 2 diabetes. Current recommendations to prevent type 2 diabetes center on lifestyle modifications, such as diet and exercise. Clinical trials have established the efficacy of lifestyle intervention, as well as pharmacologic interventions that target glycemic control or fat metabolism. However, diabetes did develop in a substantial percentage of individuals who received intensive intervention in these trials. Thus there is an unmet need for additional strategies in high-risk individuals. Recent data suggest thiazolidinediones and blockade of the endocannabinoid system represent novel therapeutic approaches that may be used for the prevention of diabetes.     

From type 2 diabetes to metabolic X syndrome

The more and more exact and simple determination of insulin provides an opportunity for exploration of the states of insulin resistance. It turned out hereby that the so-called type 1 diabetes is merely a consequence of insulin deficiency and it occurs mainly in the young. In contrary, the so-called type 2 diabetes is a multifactorial, often hyperinsulinaemic condition of insulin resistance and it occurs mainly in the adults. Furthermore, the epidemiological observations of the last decades elucidated that insulin resistance and compensating hyperinsulinaemia are common not only in type 2 diabetes but in other conditions as in ischaemic vascular diseases, hypertension, obesity, lipid alterations, coagulation disturbances, too. It became evident that the so-called late vascular complications of diabetes mellitus may develop before or without the existance of any disturbances in carbohydrate metabolism. These facts encouraged the recognition of metabolic syndrome-X. According to this hypothesis, insulin resistance and compensatorial hyperinsulinaemia are the causes of atherosclerosis, hypertension, upper body obesity, dyslipidaemia, type 2 diabetes and disturbances of coagulation. Following the last years, it became evident that hyperuricaemia, microalbuminuria and even type A personality are common in this syndrome of insulin resistance.     

Basic disturbances in skeletal muscle fatty acid metabolism in obesity and type 2 diabetes mellitus

The present article addresses the hypothesis that disturbances in skeletal muscle fatty acid handling in abdominal obesity and type 2 diabetes mellitus may play a role in the aetiology of increased adipose tissue stores, increased triacylglycerol storage in skeletal muscle and skeletal muscle insulin resistance. The uptake and/or oxidation of fatty acids have been shown to be impaired during post-absorptive conditions in abdominally-obese subjects and/or subjects with type 2 diabetes. Also, human studies have shown that muscle of subjects that are (abdominally) obese and/or have type 2 diabetes is characterized by an inability to increase fatty acid uptake and/or fatty acid oxidation during beta-adrenergic stimulation and exercise. This disturbance in fat oxidation may promote, on one hand, the development of increased adipose tissue stores and obesity. On the other hand, fatty acids that are taken up by muscle and not oxidized may increase triacylglycerol storage in muscle, which has been associated with skeletal-muscle insulin resistance. Disturbances in the capacity to increase fat oxidation during post-absorptive conditions, beta-adrenergic stimulation and exercise in subjects who are obese and/or have type 2 diabetes persist after weight reduction, indicating that the diminished fat oxidation may be a primary factor leading to the obese and/or insulin-resistant state rather than an adaptational response. Clearly, the precise sequence of events leading to an increased adiposity and insulin resistance in obesity and type 2 diabetes mellitus is not yet fully understood.     

Adipose tissue: a storage and secretory organ

The adipose tissue plays a fundamental role in maintaining the energy balance in mammals. During periods of high energy intake, the adipocytes store energy in the form of fat (triglycerides), which can be mobilized as free fatty acids during energy deprivation. Adipose tissue can no longer be considered only as a passive tissue that simply stores energy. Some recent discoveries have made it evident that this is a very active endocrine tissue that secretes important molecules related to different processes such as the immune response (TNF alpha) the regulation of food intake and expenditure of energy (leptin, Acrp30/adipoQ) and the vascular function (angiotensin and plasminogen activator inhibitor type 1). Alterations in the growth, development and function of the adipose tissue might therefore be involved in the development of different pathologies such as obesity, insulin resistance and type 2 diabetes, hypertension and atherosclerosis. A deeper understanding of the adipose tissue (morphology, development-adipogenesis, role in the metabolism and in the regulation of body weight, endocrine functions.) is needed for an adequate study of the underlying aspects in the development of obesity.     

Gene expression profile in obesity and type 2 diabetes mellitus

Obesity is an important component of metabolic syndrome X and predisposes to the development of type 2 diabetes mellitus. The incidence of obesity, type 2 diabetes mellitus and metabolic syndrome X is increasing, and the cause(s) for this increasing incidence is not clear. Although genetics could play an important role in the higher prevalence of these diseases, it is not clear how genetic factors interact with environmental and dietary factors to increase their incidence. We performed gene expression profile in subjects with obesity and type 2 diabetes mellitus with and without family history of these diseases. It was noted that genes involved in carbohydrate, lipid and amino acid metabolism pathways, glycan of biosynthesis, metabolism of cofactors and vitamin pathways, ubiquitin mediated proteolysis, signal transduction pathways, neuroactive ligand-receptor interaction, nervous system pathways, neurodegenerative disorders pathways are upregulated in obesity compared to healthy subjects. In contrast genes involved in cell adhesion molecules, cytokine-cytokine receptor interaction, insulin signaling and immune system pathways are downregulated in obese. Genes involved in signal transduction, regulation of actin cytoskeleton, antigen processing and presentation, complement and coagulation cascades, axon guidance and neurodegenerative disorders pathways are upregulated in subjects with type 2 diabetes with family history of diabetes compared to those who are diabetic but with no family history. Genes involved in oxidative phosphorylation, immune, nervous system, and metabolic disorders pathways are upregulated in those with diabetes with family history of diabetes compared to those with diabetes but with no family history. In contrast, genes involved in lipid and amino acid pathways, ubiquitin mediated proteolysis, signal transduction, insulin signaling and PPAR signaling pathways are downregulated in subjects with diabetes with family history of diabetes. It was noted that genes involved in inflammatory pathway are differentially expressed both in obesity and type 2 diabetes. These results suggest that genes concerned with carbohydrate, lipid and amino acid metabolic pathways, neuronal function and inflammation play a significant role in the pathobiology of obesity and type 2 diabetes.