The clinical potential of adipogenesis and obesity-related microRNAs

Obesity is a growing health problem commonly associated with numerous metabolic disorders including type 2 diabetes, hypertension, cardiovascular disease, and some forms of cancer. The burden of obesity and associated cardiometabolic diseases are believed to arise through complex interplay between genetics and epigenetics predisposition, nutrition, environment, and lifestyle. However, the molecular basis and the repertoire of obesity-affecting factors are still unknown. Emerging evidence is connecting microRNAs (miRNAs) dysregulation with adipogenesis and obesity. Alteration in miRNAs expression could result in changes in the pattern of genes controlling a range of biological processes including inflammation, lipid metabolism, insulin resistance and adipogenesis. Hence, understanding exact roles of miRNAs as well as the degree of their contribution to the regulation of adipogenesis and fat cell development in obesity would provide new therapeutic targets for the development of novel and effective anti-obesity drugs. The objective of the current review is to: (i) discuss some of the latest development on relevant miRNAs dysregulation mainly in human adipogenesis and obesity, (ii) emphasize the role of circulating miRNAs as new promising therapeutics and attractive potential biomarkers for treating obesity and associated risk factor diseases, (iii) describe how dietary factors may influence obesity through modulation of miRNAs expression, (iv) highlight some of the actual limitations to the promise of miRNAs as novel therapeutics as well as to their translation for the benefit of patients, and finally (v) provide recommendations for future research on miRNA-based therapeutics that could lead to a breakthrough in the treatment of obesity and its associated pathologies.     

Neurodegenerative disease and obesity: what is the role of weight loss and bariatric interventions?

Neurodegenerative diseases are amongst the leading causes of worldwide disability, morbidity and decreased quality of life. They are increasingly associated with the concomitant worldwide epidemic of obesity. Although the prevalence of both AD and PD continue to rise, the available treatment strategies to combat these conditions remain ineffective against an increase in global neurodegenerative risk factors. There is now epidemiological and mechanistic evidence associating obesity and its related disorders of impaired glucose homeostasis, type 2 diabetes mellitus and metabolic syndrome with both AD and PD. Here we describe the clinical and molecular relationship between obesity and neurodegenerative disease. Secondly we outline the protective role of weight loss, metabolic and caloric modifying interventions in the context of AD and PD. We conclude that the application of caloric restriction through dietary changes, bariatric (metabolic) surgery and gut hormone therapy may offer novel therapeutic strategies against neurodegenerative disorders. Investigating the protective mechanisms of weight loss, metabolic and caloric modifying interventions can increase our understanding of these major public health diseases and their management.     

Metabolic complications of obesity

The rising prevalence of obesity is accompanied by an increasing number of patients with the metabolic complications of obesity. The major complications come under the heading of the metabolic syndrome. This syndrome is characterized by plasma lipid disorders (atherogenic dyslipidemia), raised blood pressure, elevated plasma glucose, and a prothrombotic state. The clinical consequences of the metabolic syndrome are coronary heart disease and stroke, type 2 diabetes and its complications, fatty liver, cholesterol gallstones, and possibly some forms of cancer. At the heart of the metabolic syndrome is insulin resistance, which represents a generalized derangement in metabolic processes. Obesity is the predominant factor leading to insulin resistance, although other factors play a role. The mechanistic link between insulin resistance and the metabolic syndrome is complex. The relationship is modulated by yet other factors, such as physical activity, body fat distribution, hormones, and a person's genetic polymorphic architecture. A better understanding of the molecular basis of this relationship is needed to suggest new targets for prevention and treatment of the complications of obesity. In addition, understanding at the clinical level will lead to improved management of these complications.     

Endocannabinoid system overactivity and the metabolic syndrome: Prospects for treatment

The endocannabinoid system (ECS) plays a physiologic role in modulating energy balance, feeding behavior, lipoprotein metabolism, insulin sensitivity, and glucose homeostasis, which when dysregulated can all contribute to cardiometabolic risk. Evidence has suggested that the ECS is overactive in human obesity and in animal models of genetic and diet-induced obesity. ECS stimulation centrally and peripherally drives metabolic processes that mimic the metabolic syndrome. These findings have led to the development of potential novel therapeutic targets, including the drug rimonabant, a selective CB1 receptor antagonist, which has been shown to promote weight loss, reduce inflammation, improve dyslipidemia, and improve glucose homeostasis.     

Lipodystrophies: rare disorders causing metabolic syndrome.

Recent advances in the understanding of the molecular basis of genetic lipodystrophies have promoted understanding of how adipose tissue disorders can cause the metabolic syndrome and its complications. These discoveries hold promise for elucidating pathways and mechanisms by which common disorders of obesity cause metabolic complications. Novel therapeutic approaches for patients with lipodystrophies also may have implications for treatment of the metabolic syndrome in patients with regional adiposity. This article reviews these recent advances in our knowledge of the clinical features, metabolic abnormalities, and pathogenetic or other bases of various types of lipodystrophies.     

Nuclear receptors as drug targets in metabolic diseases: new approaches to therapy.

Nuclear receptors represent novel targets for the development of therapeutic agents for the treatment of numerous diseases, including type 2 diabetes, obesity dyslipidemia, atherosclerosis and the metabolic syndrome. There have been many recent advances in the development of new therapeutic agents for a subset of these receptors, including the peroxisome proliferator-activated receptors, the liver X receptors and the farnesoid X receptor. To date, the synthesis of selective modulators that regulate the activity of these receptors has been empirical. However, a detailed understanding of the molecular basis for selective modulation, as well as new insights into the biology of these receptors, might open the door to the rational design of a new generation of therapeutic agents with improved safety and efficacy.     

Hypothalamische Entzündung und metabolisches Syndrom

Overweight and obesity are two key factors in development of the metabolic syndrome. In recent years the major focus was directed towards elucidating how impairment of the central nervous system affects food intake and the development of obesity and insulin resistance. It has been shown in animal models and in humans that overconsumption of an energy-dense, high-fat diet leads to fundamental structural and functional changes of hypothalamic nuclei which govern eating behavior. Several recent scientific studies suggested that these nutritionally induced hypothalamic effects and changes, i.e. apoptosis of hypothalamic neurons and glial cells and subsequent local inflammatory processes, modulate eating behavior and metabolism in a defined way paving the way for development of obesity and eventually also the metabolic syndrome. This article summarizes findings from current related studies, introduces some of the underlying molecular mechanisms and shows how this knowledge might be used to develop novel treatment options for patients suffering from obesity and the metabolic syndrome.     

A systematic review of the association of neuregulin 4, a brown fat–enriched secreted factor,with obesity and related metabolic disturbances

Neuregulin 4 (Nrg4), a novel brown fat–enriched hormone, plays a key role in the modulation of glucose and lipid metabolism and energy balance. Recent data have demonstrated that the expression of Nrg4 is substantially down‐regulated in mouse and human obesity, making its regulatory aspect intriguing. Because of the close relationship between Nrg4, obesity, and associated metabolic diseases, this systematic review aimed to assess the association of Nrg4 with obesity and related metabolic disturbances, emphasizing its possible mechanisms of action in these disorders. We searched PubMed/Medline, ScienceDirect, Scopus, EMBASE, ProQuest, and Google Scholar up until June 2019. The evidence reviewed here indicates that Nrg4 may contribute to the prevention of obesity and related metabolic complications by elevating brown adipose tissue activity, increasing the expression of thermogenic markers, decreasing the expression of lipogenic/adipogenic genes, exacerbating white adipose tissue browning, increasing the number of brite/beige adipocytes, promoting hepatic fat oxidation and ketogenesis, inducing neurite outgrowth, enhancing blood vessels in adipose tissue, increasing the circulatory levels of healthy adipokines, and improving glucose homeostasis. Thus, Nrg4 appears to be a novel therapeutic strategy for the treatment of obesity and associated metabolic complications. However, prospective cohort studies are warranted to confirm these outcomes.     

脂肪细胞关联基因与老年肥胖代谢性疾病

肥胖及肥胖代谢综合征作为老年人常见病和合并症目前已不再足某些发达国家或地区的问题,它已经成为全球各个国家都将面l临的重大医学问题和健康问题。而且,肥胖可引发老年代谢性疾病、呼吸系统疾病、心血管系统疾病以及骨关节退行性变、性激素分泌失调、静脉淤滞、深静脉血栓形成及肿瘤的发生和发展等,其潜在的健康影响和生命威胁难以估量,给国家带来的社会问题和经济损失也无法计算。而某些脂肪细胞关联基因及肥胖基因与人类肥胖及肥胖代谢综合征密切相关,因此,对这些肥胖基因表达及关联因素实施有效调控,对控制人类肥胖及肥胖代谢综合征的发生、发展及转归具有重要临床意义。正是基于这些,本文通过对肥胖相关基因及其与相关临床疾病关系的文献进行综述,希望未来能够对以这些肥胖基因作为靶点的肥胖预防和治疗药物的设计提供某些依据并奠定一定基础。     

Epigenetic regulation of N6-methyladenosine modifications in obesity

Obesity is a serious health issue in the world and is related to a higher risk of suffering metabolic diseases. Understanding the molecular basis of obesity is critical to identify new targets to treat obesity and obesity-associated metabolic diseases. N6-methyladenosine (m6A) modification is the most common form of ribonucleic acid modification, which has attracted increasing interest of researchers in recent years, as it is reported that m6A has vital functions in diseases and everyday life activities. Recent studies showed that m6A modification was decreased in obese adipose tissue, and appeared to play a regulatory role in many obesity-associated biological processes, including adipogenesis, lipid metabolism and insulin resistance. In this review, we discussed the emerging advances in m6A modification in obesity to provide a novel therapeutic strategy for fighting against obesity.     

Telmisartan prevents obesity and increases the expression of uncoupling protein 1 in diet-induced obese mice

The aim of the present study was to clarify the effect of telmisartan, an angiotensin II receptor blocker, on the development of obesity and related metabolic disorders in diet-induced obese mice. Treatment with telmisartan dissolved in drinking water at a dosage of 5 mg/kg per day for 14 days attenuated the diet-induced weight gain without affecting food intake in diet-induced obese mice compared with controls using nontreated water. Telmisartan treatment decreased the weight of visceral adipose tissue and the triglyceride content in the liver and skeletal muscle. In addition, hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in diet-induced obese mice all improved with telmisartan treatment. Furthermore, telmisartan treatment increased adiponectin mRNA in visceral white adipose tissue and was associated with a concomitant change in the serum adiponectin level. In contrast, the treatment reduced the serum level of resistin. Finally, telmisartan treatment increased the mRNA expression of uncoupling protein 1 in brown adipose tissue and was accompanied by an increase in oxygen consumption. In conclusion, telmisartan treatment might prevent the development of obesity and related metabolic disorders by altering the levels of adiponectin, resistin, and uncoupling protein 1 in diet-induced obese mice. Our results indicate that telmisartan can be used as a therapeutic tool for metabolic syndrome, including visceral obesity.     

Interventional metabology: A review of bariatric arterial embolization and endovascular denervation for treating metabolic disorders

The rising prevalence of metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM) poses a major challenge to global health. Existing therapeutic approaches have limitations, and there is a need for new, safe, and less invasive treatments. Interventional metabolic therapy is a new addition to the treatment arsenal for metabolic disorders. This review focuses on two interventional techniques: bariatric arterial embolization (BAE) and endovascular denervation (EDN). BAE involves embolizing specific arteries feeding ghrelin-producing cells to suppress appetite and promote weight loss. EDN targets nerves that regulate metabolic organs to improve glycemic control in T2DM patients. We describe the current state of these techniques, their mechanisms of action, and the available safety and effectiveness data. We also propose a new territory called “Interventional Metabology” to encompass these and other interventional approaches to treating metabolic disorders.     

Ghrelin, obesity and diabetes

The high prevalence of obesity and diabetes will lead to higher rates of morbidity and mortality. The search for drugs to treat these metabolic disorders has, therefore, intensified. The stomach-derived peptide ghrelin regulates food intake and body weight. Recent work suggests that ghrelin also controls glucose metabolism. In addition, current evidence suggests that most of the actions of ghrelin could contribute to the metabolic syndrome. The ghrelin signaling system is, therefore, a promising target for the development of new drugs for the treatment of obesity and diabetes. Agents that block the ghrelin signaling system might be especially useful targets. This Review summarizes the potential and the limitations of ghrelin as a tool to better understand, prevent and treat obesity and diabetes.     

网膜素与肥胖及胰岛素抵抗的关系

网膜素是新近发现的一种脂肪细胞因子,特异性表达于内脏脂肪组织.目前研究表明,网膜素能促进皮下和网膜脂肪细胞胰岛素刺激的葡萄糖转运和蛋白激酶B磷酸化,且与肥胖相关,在调节糖代谢中具有一定作用.因此,对网膜素的表达、作用机制及生物学功能的深入研究,有助于进一步阐明肥胖、代谢综合征及糖尿病等的发病机制,从而为这些疾病的治疗提供新的方向.     

网膜素与肥胖及胰岛素抵抗的关系

网膜素是新近发现的一种脂肪细胞因子,特异性表达于内脏脂肪组织.目前研究表明,网膜素能促进皮下和网膜脂肪细胞胰岛素刺激的葡萄糖转运和蛋白激酶B磷酸化,且与肥胖相关,在调节糖代谢中具有一定作用.因此,对网膜素的表达、作用机制及生物学功能的深入研究,有助于进一步阐明肥胖、代谢综合征及糖尿病等的发病机制,从而为这些疾病的治疗提供新的方向.     

网膜素与肥胖及胰岛素抵抗的关系

网膜素是新近发现的一种脂肪细胞因子,特异性表达于内脏脂肪组织.目前研究表明,网膜素能促进皮下和网膜脂肪细胞胰岛素刺激的葡萄糖转运和蛋白激酶B磷酸化,且与肥胖相关,在调节糖代谢中具有一定作用.因此,对网膜素的表达、作用机制及生物学功能的深入研究,有助于进一步阐明肥胖、代谢综合征及糖尿病等的发病机制,从而为这些疾病的治疗提供新的方向.