Past, present and future strategies to study the genetics of body weight regulation.

Genetic advances have made remarkable progress towards our understanding of body weight regulation. Much of our current knowledge has come from the cloning and characterisation of the genes responsible for obesity syndromes in the mouse, and the identification of homologous mutations causing rare forms of obesity in humans. Gene targeting experiments in mice have been instrumental in confirming the importance of many genes in the aetiology of obesity, and the existence of a fundamental physiological pathway that controls energy balance is becoming clear. The genetic determinants that underlie common forms of human obesity are largely polygenic, with most genes producing small effects. Thus, elucidating the many genetic determinants of obesity is a current challenge for modern geneticists. Despite the inherent difficulties, progress has been made through linkage/association studies and a genetic map of quantitative trait loci for human obesity is beginning to emerge. Obesity research is now very much in a transition period. Not so long ago, access to high throughput screening, as well as microarray and proteomic techniques, was prohibitively expensive and available only to the few. In recent years, these technologies have become more accessible to the larger scientific community and, in this paper, we will discuss how such technological advances are likely to drive the next wave of progress in obesity research. For example, large-scale mutagenesis screens in rodents coupled with high throughput screening are likely to emerge as important technologies for identifying genes previously unexpected to be involved in body weight regulation. Furthermore, applications of microarray and proteomic techniques will further refine our understanding of currently known peptides as well as identify novel pathways and molecules which are involved in energy homeostasis.     

Melanocortin and leptin signaling systems: central regulation of catabolic energy balance

The recent cloning of the ob gene (leptin) has revolutionized our understanding of obesity and the underlying factors that govern weight homeostasis. There is growing evidence that long term food intake regulation is controlled by the central nervous system by a number of peptide hormones in response to changes in leptin levels. Studies of these hormones, using both genetic and pharmacological approaches, have provided a foundation for decoding the molecular logic of the neuronal circuits which regulate food intake control and energy balance. A review of the current progress in the melanocortin-4 receptor pathway, with particular emphasis on its relation to leptin, neuropeptide Y and other obesity hormones known to modulate weight homeostasis, is presented.     

Melanocortin and leptin signaling systems: Central regulation of catabolic energy balance

Abstract

The recent cloning of the ob gene (leptin) has revolutionized our understanding of obesity and the underlying factors that govern weight homeostasis. There is growing evidence that long term food intake regulation is controlled by the central nervous system by a number of peptide hormones in response to changes in leptin levels. Studies of these hormones, using both genetic and pharmacological approaches, have provided a foundation for decoding the molecular logic of the neuronal circuits which regulate food intake control and energy balance. A review of the current progress in the melanocortin-4 receptor pathway, with particular emphasis on its relation to leptin, neuropeptide Y and other obesity hormones known to modulate weight homeostasis, is presented.     

Monogenic disorders of obesity and body fat distribution.

Recently, great progress has been made towards understanding the molecular basis of body fat regulation. Identification of mutations in several genes in spontaneous monogenic animal models of obesity and development of transgenic models have indicated the physiological roles of many genes in the regulation of body fat distribution. In humans, mutations in leptin, leptin receptor, prohormone convertase 1 (PC1), pro-opiomelanocortin (POMC), melanocortin 4-receptor (MC4-R), and peroxisome proliferator-activated receptor (PPAR) gamma2 genes have been described in patients with severe obesity. Most of these obesity disorders exhibit a distinct phenotype with varying degrees of hypothalamic and pituitary dysfunction and a recessive inheritance, whereas MC4-R mutation has a nonsyndromic phenotype with dominant inheritance. These mutations suggest the critical role of central signaling systems composed of leptin/leptin receptor and alpha-melanocyte stimulating hormone/MC4-R in human energy homeostasis. Although the genetic basis of monogenic disorders of body fat distribution, such as congenital generalized lipodystrophy and familial partial lipodystrophy, Dunnigan variety, is still unknown, the genes for these have recently been localized to chromosomes 9q34 and 1q21-22, respectively. The advances in our knowledge of the phenotypic manifestations and underlying molecular mechanisms of genetic body fat disorders may lead to better treatment and prevention of obesity and other disorders of adipose tissue in the future.     

Molecular genetics of human obesity: A comprehensive review

Obesity and its related health complications is a major problem worldwide. Hypothalamus and their signalling molecules play a critical role in the intervening and coordination with energy balance and homeostasis. Genetic factors play a crucial role in determining an individual's predisposition to the weight gain and being obese. In the past few years, several genetic variants were identified as monogenic forms of human obesity having success over common polygenic forms. In the context of molecular genetics, genome-wide association studies (GWAS) approach and their findings signified a number of genetic variants predisposing to obesity. However, the last couple of years, it has also been noticed that alterations in the environmental and epigenetic factors are one of the key causes of obesity. Hence, this review might be helpful in the current scenario of molecular genetics of human obesity, obesity-related health complications (ORHC), and energy homeostasis. Future work based on the clinical discoveries may play a role in the molecular dissection of genetic approaches to find more obesity-susceptible gene loci.     

Protein kinase C-beta: An emerging connection between nutrient excess and obesity

There is currently a global epidemic of obesity as a result of recent changes in lifestyle. Excess body fat deposition is caused by an imbalance between energy intake and energy expenditure due to interactions between genetic and environmental factors. The signals and biological mechanisms that trigger fat accumulation by disrupting energy homeostasis are not well understood. There is considerable evidence now supporting a possible role of protein kinase C beta (PKCβ) in energy homeostasis. This review highlights recent findings on the role of PKCβ activation in the genesis and progression of obesity, and of PKCβ repression in mediating the beneficial effects of physical exercise. Available data support a model in which adipose PKCβ activation is among the initiating events that disrupt mitochondrial function through interaction with p66^shc and amplify fat accumulation and adipose dysfunction, with systemic consequences. Manipulation of PKCβ levels, activity, or signaling could provide a therapeutic approach to combat obesity and associated metabolic disorders.     

Adaptive thermogenesis by dietary n-3 polyunsaturated fatty acids: Emerging evidence and mechanisms

Brown/beige fat plays a crucial role in maintaining energy homeostasis through non-shivering thermogenesis in response to cold temperature and excess nutrition (adaptive thermogenesis). Although numerous molecular and genetic regulators have been identified, relatively little information is available regarding thermogenic dietary molecules. Recently, a growing body of evidence suggests that high consumption of n-3 polyunsaturated fatty acids (PUFA) or activation of GPR120, a membrane receptor of n-3 PUFA, stimulate adaptive thermogenesis. In this review, we summarize the emerging evidence that n-3 PUFA promote brown/beige fat formation and highlight the potential mechanisms whereby n-3 PUFA require GPR120 as a signaling platform or act independently. Human clinical trials are revisited in the context of energy expenditure. Additionally, we explore some future perspective that n-3 PUFA intake might be a useful strategy to boost or sustain metabolic activities of brown/beige fat at different lifecycle stages of pregnancy and senescence. Given that a high ratio of n-6/n-3 PUFA intake is associated with the development of obesity and type 2 diabetes, understanding the impact of n-6/n-3 ratio on energy expenditure and adaptive thermogenesis will inform the implementation of a novel nutritional strategy for preventing obesity.     

Adipocytes under assault: Environmental disruption of adipose physiology

The burgeoning obesity epidemic has placed enormous strains on individual and societal health mandating a careful search for pathogenic factors, including the contributions made by endocrine disrupting chemicals (EDCs). In addition to evidence that some exogenous chemicals have the capacity to modulate classical hormonal signaling axes, there is mounting evidence that several EDCs can also disrupt metabolic pathways and alter energy homeostasis. Adipose tissue appears to be a particularly important target of these metabolic disruptions. A diverse array of compounds has been shown to alter adipocyte differentiation, and several EDCs have been shown to modulate adipocyte physiology, including adipocytic insulin action and adipokine secretion. This rapidly emerging evidence demonstrating that environmental contaminants alter adipocyte function emphasizes the potential role that disruption of adipose physiology by EDCs may play in the global epidemic of metabolic disease. Further work is required to better characterize the molecular targets responsible for mediating the effects of EDCs on adipose tissue. Improved understanding of the precise signaling pathways altered by exposure to environmental contaminants will enhance our understanding of which chemicals pose a threat to metabolic health and how those compounds synergize with lifestyle factors to promote obesity and its associated complications. This knowledge may also improve our capacity to predict which synthetic compounds may alter energy homeostasis before they are released into the environment while also providing critical evidentiary support for efforts to restrict the production and use of chemicals that pose the greatest threat to human metabolic health. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.     

Long non-coding RNAs regulation in adipogenesis and lipid metabolism: Emerging insights in obesity

Obesity is a widespread health problem that brings about various adipose tissue dysfunctions. The balance of energy storage and energy expenditure is critical for normal fat accumulation and lipid metabolism. Therefore, understanding the molecular basis of adipogenesis and thermogenesis is essential to maintain adipose development and lipid homeostasis. Increasing evidence demonstrated that lncRNAs (long non-coding RNAs), a class of non-protein coding RNAs of >200 nucleotides in length, are identified as key regulators in obesity-related biological processes through diverse regulatory mechanisms. In this review, we concentrate on recent and relevant studies on the roles of lncRNAs in regulation of white adipogenesis, brown adipocyte differentiation and lipid metabolism. In addition, the diagnostic and therapeutic potential of lncRNAs is highlighted, and that will make recommendations for the future application of lncRNAs in the treatment of obesity.     

Vaspin (serpinA12) in obesity,insulin resistance,and inflammation

While genome‐wide association studies as well as candidate gene studies have revealed a great deal of insight into the contribution of genetics to obesity development and susceptibility, advances in adipose tissue research have substantially changed the understanding of adipose tissue function. Its perception has changed from passive lipid storage tissue to active endocrine organ regulating and modulating whole‐body energy homeostasis and metabolism and inflammatory and immune responses by secreting a multitude of bioactive molecules, termed adipokines. The expression of human vaspin (serpinA12) is positively correlated to body mass index and insulin sensitivity and increases glucose tolerance in vivo, suggesting a compensatory role in response to diminished insulin signaling in obesity. Recently, considerable insight has been gained into vaspin structure, function, and specific target tissue‐dependent effects, and several lines of evidence suggest vaspin as a promising candidate for drug development for the treatment of obesity‐related insulin resistance and inflammation. These will be summarized in this review with a focus on molecular mechanisms and pathways. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.     

Drosophila as a model to study the genetic mechanisms of obesity-associated heart dysfunction

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.     

代谢病相关的遗传工程小鼠模型

糖尿病及肥胖症等代谢性疾病已成为影响人类健康的主要疾病,属于多基因所致的代谢综合征,遗传模式复杂多样,至今仍所知甚少。理想的实验动物模型是我们深入了解代谢病病因、遗传及环境因素的必要工具,并且可以用来研究验证新的治疗药物。近年来,已经获得了大量的遗传工程动物模型,包括转基因、基因敲除模型等遗传工程动物,对于代谢性疾病的研究意义重大。本文主要介绍近年来应用较多的糖尿病及肥胖相关的遗传工程小鼠模型遗传特征及应用。     

Sleep and circadian rhythms: key components in the regulation of energy metabolism

In this review, we present evidence from human and animal studies to evaluate the hypothesis that sleep and circadian rhythms have direct impacts on energy metabolism, and represent important mechanisms underlying the major health epidemics of obesity and diabetes. The first part of this review will focus on studies that support the idea that sleep loss and obesity are "interacting epidemics." The second part will discuss recent evidence that the circadian clock system plays a fundamental role in energy metabolism at both the behavioral and molecular levels. These lines of research must be seen as in their infancy, but nevertheless, have provided a conceptual and experimental framework that potentially has great importance for understanding metabolic health and disease.     

Developmental mechanisms and experimental models to understand forebrain malformative diseases

The development of the central nervous system can be divided into a number of phases, each of which can be subject of genetic or epigenetic alterations that may originate particular developmental disorders. In recent years, much progress has been made in elucidating the molecular and cellular mechanisms by which the vertebrate forebrain develops. Therefore, our understanding of major developmental brain disorders such as cortical malformations and neuronal migration disorders has significantly increased. In this review, we will describe the major stages in forebrain morphogenesis and regionalization, with special emphasis on developmental molecular mechanisms derailing telencephalic development with subsequent damage to cortical function. Because animal models, mainly mouse, have been fundamental for this progress, we will also describe some characteristic mouse models that have been capital to explore these molecular mechanisms of malformative diseases of the human brain. Although most of the genes involved in the regulation of basic developmental processes are conserved among vertebrates, the extrapolation of mouse data to corresponding gene expression and function in humans needs careful individual analysis in each functional system.     

Developmental mechanisms and experimental models to understand forebrain malformative diseases

The development of the central nervous system can be divided into a number of phases, each of which can be subject of genetic or epigenetic alterations that may originate particular developmental disorders. In recent years, much progress has been made in elucidating the molecular and cellular mechanisms by which the vertebrate forebrain develops. Therefore, our understanding of major developmental brain disorders such as cortical malformations and neuronal migration disorders has significantly increased. In this review, we will describe the major stages in forebrain morphogenesis and regionalization, with special emphasis on developmental molecular mechanisms derailing telencephalic development with subsequent damage to cortical function. Because animal models, mainly mouse, have been fundamental for this progress, we will also describe some characteristic mouse models that have been capital to explore these molecular mechanisms of malformative diseases of the human brain. Although most of the genes involved in the regulation of basic developmental processes are conserved among vertebrates, the extrapolation of mouse data to corresponding gene expression and function in humans needs careful individual analysis in each functional system.     

Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation

This review focuses on adipose tissue biology and introduces the concept of adipose tissue plasticity and expandability as key determinants of obesity-associated metabolic dysregulation. This concept is fundamental to our understanding of adipose tissue as a dynamic organ at the center of nutritional adaptation. Here, we summarize the current knowledge of the mechanisms by which adipose tissue can affect peripheral energy homeostasis, particularly in the context of overnutrition. Two mechanisms emerge that provide a molecular understanding for obesity-associated insulin resistance. These are a) the dysregulation of adipose tissue expandability and b) the abnormal production of adipokines. This knowledge has the potential to pave the way for novel therapeutic concepts and strategies for managing and/or correcting complications associated with obesity and the metabolic syndrome.