Human Weight Regulation Research Articles

MC4R gene polymorphisms for classification of growth efficiency and carcass measurements in two rabbit breeds in Egypt

Melanocortin 4 receptor (MC4R), a protein derived from the MC4R gene, is involved in feed intake, metabolism control, and body weight regulation in humans. The purpose of this research was to explore MC4R polymorphisms alongside metabolic marker changes and their relationship with growth and carcass measurements in rabbits. Using synthetic line V (V-line) and Baladi Black rabbit breeds (60 rabbits per breed), blood samples were collected for DNA extraction and biochemical analysis. The polymerase chain reaction (PCR) product of MC4R (493 bp) revealed five nonsynonymous single nucleotide polymorphisms (SNPs; submitted to GenBank with accession numbers gb|MT832144|, gb|MT832145|, and gb|MT832146|). Four SNPs were characteristic of the V-line breed, and one was characteristic of the Baladi Black. For classification of the defined SNP-dependent groups within and between breeds, a discriminant analysis model correctly classified a percentage of cases with the following predictor variables: 90.8% for body weight at 5–14 weeks of age; 85% for feed consumption, daily feed intake, and feed conversion ratio; and 93.3% for carcass measurements (for which hind part weight, liver weight, and liver percentage were the best predictors in both breeds). There were significant differences between and within V-line and Baladi Black breeds in agreement with metabolic biochemical marker profiles and the defined SNPs. The identified SNPs in the MC4R gene and profile of the investigated metabolic biomarkers could be used as candidates and reference for the effective characterization of the two rabbit breeds. This study could therefore facilitate the introduction of markerassisted selection for growth performance characteristics in rabbits.

Does the gut microbiota hold the key to the obesity crisis? A perspective piece

Emerging evidence indicates that the gut microbiota relate to the onset and maintenance of obesity via several pathophysiological mechanisms, all of which are influenced by the host diet. The rapid shift towards Western-typical diets at a global scale may be contributing to gut dysbiosis, and consequently fuelling the global obesity crisis. Further mechanistic understanding of the influence of the gut microbiota in weight regulation in humans may lend itself to the development of more efficacious treatments.

OR33-06 Potential Role of Mutations in TBX3 in Human Weight Regulation

Introduction: Tbx3 has been shown to play a role in the terminal specification of hypothalamic melanocortin neurons during neonatal development & in maintaining the plasticity of their peptidergic role in adulthood in animal experiments (1). The absence of humans with biallelic mutations in TBX3 & the conservation of the critical domains across species emphasizes its essential role in life. Heterozygous mutations in humans have been associated with ulnar mammary syndrome (UMS) with a spectrum of phenotype including obesity. Based on these observations, we hypothesized that heterozygous mutations in the conserved regions of TBX3 may play an important role in the weight regulation pathway in humans. Methods: The Genetics of Early Childhood Obesity (GECO) study enrolls children with severe (BMI > 120% of 95th %tile of CDC reference) early onset (< 6 years) obesity. Whole exome sequencing (WES) was performed in a subset of proband-parent trios. Peripheral mononuclear cells (PBMCs) from selected families were collected to generate induced pluripotent stem cells using non-integrating Sendai virus. Differentiation into disease-relevant hypothalamic neurons was performed using the published protocol (2). Loss-of-function models & isogenic controls were created using CRISPR/Cas9 & their cellular/molecular phenotypes were obtained at several time points during the course of differentiation. Results: We have identified a family with heterozygous mutation in TBX3 (p.His205Tyr, c.613 C>T, g.115118728 G>A). The proband is an 11-year old boy with morbid obesity (BMI 43.9 kg/m2, BMIz + 3.25), advanced bone age, precocious puberty & type 2 diabetes. Trio analysis ruled out recessive & compound heterozygote causative variants, & none of the identified de novo variants were considered pathogenic. His mother suffers from severe obesity (BMI 38 kg/m2 post-bariatric surgery) supporting an autosomal dominant inheritance of the phenotype. The putative causal variant in TBX3 segregates in the proband, mother & maternal grandmother. Located in the DNA binding domain of T-box, the variant is predicted to be deleterious by 4 in silico algorithms & rare in population-based databases (mean allele frequency 0.006% in gNOMAD, absent in ClinVar). Consistent with the variable penetrance of the phenotype in UMS, neither mother nor child have the classic features, but, the mother has uterine anomalies causing 6 spontaneous abortions & was unable to breast feed due to inverted nipples. Ongoing functional studies in human hypothalamic neurons suggest that a decrease in melanocortin signaling possibly explaining the phenotype in this family. Conclusions: Mutations in TBX3 in humans may have a role as a monogenic cause of obesity and disease-relevant hypothalamic stem cells can serve as models to study them. Ref: 1) Quarta et al. Nat Metab 2019, 1(2), 222-35; 2) Wang et al. JCI, 125(2): 796-808

Metabolic Factors Determining the Susceptibility to Weight Gain: Current Evidence.

There is substantial inter-individual variability in body weight change, which is not fully accounted by differences in daily energy intake and physical activity levels. The metabolic responses to short-term perturbations in energy intake can explain part of this variability by quantifying the degree of metabolic "thriftiness" that confers more susceptibility to weight gain and more resistance to weight loss. It is unclear which metabolic factors and pathways determine this human "thrifty" phenotype. This review will investigate and summarize emerging research in the field of energy metabolism and highlight important metabolic mechanisms implicated in body weight regulation in humans. Dysfunctional adipose tissue lipolysis, reduced brown adipose tissue activity, blunted fibroblast growth factor 21 secretion in response to low-protein hypercaloric diets, and impaired sympathetic nervous system activity might constitute important metabolic factors characterizing "thriftiness" and favoring weight gain in humans. The individual propensity to weight gain in the current obesogenic environment could be ascertained by measuring specific metabolic factors which might open up new pathways to prevent and treat human obesity.

Preventing Weight Gain through Tackling Sedentary Behaviour: A System Dynamics Optimization Approach

Obesity is becoming a serious problem in Malaysia as it has been rated as the highest among Asian countries. Many factors have contributed to obesity and sedentary behavior is one of the cause. The objective of the research is to analyze the impact of sedentary behavior to prevent weight gain among adult population in Malaysia. The system dynamics (SD) approach of stockflow diagram was used to quantitatively model the impact of eating and activity behavior on the complex of human weight regulation system. The modeling stage involved with the experimentation process where the developed model was used to investigate the impacts of changes in duration and frequency of sedentary behaviour on weight and prevalence of obesity implications. In this paper, the baserun results is presented where it shows that with increase in energy intake along with increase in sedentary behavior, the results is on weight gain. This is because the excessive of positive balance energy which accumulate in daily process will results to the increase in a weight trend for a long period if the excess energy is not burning.This paper provides evidence on the usefulness of SD optimization to assist in decision making related to achievement in population weight target. SD applied in this research is relatively new in Malaysia and has a high potential to apply to any feedback models that address the behavior cause to obesity.

Serum asprosin levels and bariatric surgery outcomes in obese adults.

Asprosin is a novel fasting-induced glucogenic and orexigenic protein hormone. The clinical function of asprosin in obesity is currently unknown. This study investigated the association between asprosin abundance and the outcome of bariatric surgery. Patients with body mass index more than 35 kg/m2 were recruited for the Obesity and Clock for Elegant Aging Registry in 2011-2016. Body weight changes, blood sugar, and asprosin were assessed in 117 patients receiving bariatric surgery and 57 non-obese subjects as normal control. Primary outcomes of excess weight loss percentage at 6 months after bariatric surgery were determined at follow-up. Asprosin levels were significantly higher in obese patients than in non-obese subjects (2360 ± 5094 vs. 307 ± 832 ng/ml, p < 0.0001). Multivariate analyses showed a significant association of asprosin abundance with excess body weight loss percentage at 6 months after surgery (p < 0.0001). After adjusted for age, sex, smoking, HbA1c, cholesterol, and triglyceride, serum asprosin level was the only independent predictor of 6 months excess weight loss percentage after bariatric surgery. Asprosin levels decreased significantly 6 months after bariatric surgery (162.2 ± 169.1 ng/ml). Furthermore, there was no association between asprosin and serum glucose levels in our study. This study provides novel evidence that higher asprosin concentrations before bariatric surgery were associated with the weight reduction magnitude at 6 months after surgery. Further studies are warranted to investigate whether asprosin has direct functions to modulate body weight regulation in humans after bariatric surgery.

Perfluoroalkyl substances and changes in body weight and resting metabolic rate in response to weight-loss diets: A prospective study.

BackgroundThe potential endocrine-disrupting effects of perfluoroalkyl substances (PFASs) have been demonstrated in animal studies, but whether PFASs may interfere with body weight regulation in humans is largely unknown. This study aimed to examine the associations of PFAS exposure with changes in body weight and resting metabolic rate (RMR) in a diet-induced weight-loss setting.Methods and findingsIn the 2-year POUNDS Lost randomized clinical trial based in Boston, Massachusetts, and Baton Rouge, Louisiana, that examined the effects of energy-restricted diets on weight changes, baseline plasma concentrations of major PFASs were measured among 621 overweight and obese participants aged 30–70 years. Body weight was measured at baseline and 6, 12, 18, and 24 months. RMR and other metabolic parameters, including glucose, lipids, thyroid hormones, and leptin, were measured at baseline and 6 and 24 months. Participants lost an average of 6.4 kg of body weight during the first 6 months (weight-loss period) and subsequently regained an average of 2.7 kg of body weight during the period of 6–24 months (weight regain period). After multivariate adjustment, baseline PFAS concentrations were not significantly associated with concurrent body weight or weight loss during the first 6 months. In contrast, higher baseline levels of PFASs were significantly associated with a greater weight regain, primarily in women. In women, comparing the highest to the lowest tertiles of PFAS concentrations, the multivariate-adjusted mean weight regain (SE) was 4.0 (0.8) versus 2.1 (0.9) kg for perfluorooctanesulfonic acid (PFOS) (Ptrend = 0.01); 4.3 (0.9) versus 2.2 (0.8) kg for perfluorooctanoic acid (PFOA) (Ptrend = 0.007); 4.7 (0.9) versus 2.5 (0.9) kg for perfluorononanoic acid (PFNA) (Ptrend = 0.006); 4.9 (0.9) versus 2.7 (0.8) kg for perfluorohexanesulfonic acid (PFHxS) (Ptrend = 0.009); and 4.2 (0.8) versus 2.5 (0.9) kg for perfluorodecanoic acid (PFDA) (Ptrend = 0.03). When further adjusted for changes in body weight or thyroid hormones during the first 6 months, results remained similar. Moreover, higher baseline plasma PFAS concentrations, especially for PFOS and PFNA, were significantly associated with greater decline in RMR during the weight-loss period and less increase in RMR during the weight regain period in both men and women. Limitations of the study include the possibility of unmeasured or residual confounding by socioeconomic and psychosocial factors, as well as possible relapse to the usual diet prior to randomization, which could have been rich in foods contaminated by PFASs through food packaging and also dense in energy.ConclusionsIn this diet-induced weight-loss trial, higher baseline plasma PFAS concentrations were associated with a greater weight regain, especially in women, possibly explained by a slower regression of RMR levels. These data illustrate a potential novel pathway through which PFASs interfere with human body weight regulation and metabolism. The possible impact of environmental chemicals on the obesity epidemic therefore deserves attention.Trial registrationClinicalTrials.gov NCT00072995

Determinants of body weight regulation in humans.

Body weight is regulated by the ability of hypothalamic neurons to orchestrate behavioral, endocrine and autonomic responses via afferent and efferent pathways to the brainstem and the periphery. Weight maintenance requires a balance between energy intake and energy expenditure. Although several components that participate in energy homeostasis have been identified, there is a need to know in more detail their actions as well as their interactions with environmental and psychosocial factors in the development of human obesity. In this review, we examine the role of systemic mediators such as leptin, ghrelin and insulin, which act in the central nervous system by activating or inhibiting neuropeptide Y, Agouti-related peptide protein, melanocortin, transcript related to cocaine and amphetamine, and others. As a result, modifications in energy homeostasis occur through regulation of appetite and energy expenditure. We also examine compensatory changes in the circulating levels of several peripheral hormones after diet-induced weight loss.

Implication of coronin 7 in body weight regulation in humans, mice and flies.

BackgroundObesity is a growing global concern with strong associations with cardiovascular disease, cancer and type-2 diabetes. Although various genome-wide association studies have identified more than 40 genes associated with obesity, these genes cannot fully explain the heritability of obesity, suggesting there may be other contributing factors, including epigenetic effects.ResultsWe performed genome wide DNA methylation profiling comparing normal-weight and obese 9–13 year old children to investigate possible epigenetic changes correlated with obesity. Of note, obese children had significantly lower methylation levels at a CpG site located near coronin 7 (CORO7), which encodes a tryptophan-aspartic acid dipeptide (WD)-repeat containing protein most likely involved in Golgi complex morphology and function. Anatomical profiling of coronin 7 (Coro7) mRNA expression in mice revealed that it is highly expressed in appetite and energy balance regulating regions, including the hypothalamus, striatum and locus coeruleus, the main noradrenergic brain site. Interestingly, we found that food deprivation in mice downregulates hypothalamic Coro7 mRNA levels, and injecting ethanol, an appetite stimulant, increased the number of Coro7 expressing cells in the locus coeruleus. Finally, by employing the genetically-tractable Drosophila melanogaster model we were able to demonstrate an evolutionarily conserved metabolic function for the CORO7 homologue pod1. Knocking down the pod1 in the Drosophila adult nervous system increased their resistance to starvation. Furthermore, feeding flies a high-calorie diet significantly increased pod1 expression.ConclusionWe conclude that coronin 7 is involved in the regulation of energy homeostasis and this role stems, to some degree, from the effect on feeding for calories and reward.

Combating obesity through healthy eating behavior: a call for system dynamics optimization.

Poor eating behavior has been identified as one of the core contributory factors of the childhood obesity epidemic. The consequences of obesity on numerous aspects of life are thoroughly explored in the existing literature. For instance, evidence shows that obesity is linked to incidences of diseases such as heart disease, type-2 diabetes, and some cancers, as well as psychosocial problems. To respond to the increasing trends in the UK, in 2008 the government set a target to reverse the prevalence of obesity (POB) back to 2000 levels by 2020. This paper will outline the application of system dynamics (SD) optimization to simulate the effect of changes in the eating behavior of British children (aged 2 to 15 years) on weight and obesity. This study also will identify how long it will take to achieve the government’s target. This paper proposed a simulation model called Intervention Childhood Obesity Dynamics (ICOD) by focusing the interrelations between various strands of knowledge in one complex human weight regulation system. The model offers distinct insights into the dynamics by capturing the complex interdependencies from the causal loop and feedback structure, with the intention to better understand how eating behaviors influence children’s weight, body mass index (BMI), and POB measurement. This study proposed a set of equations that are revised from the original (baseline) equations. The new functions are constructed using a RAMP function of linear decrement in portion size and number of meal variables from 2013 until 2020 in order to achieve the 2020 desired target. Findings from the optimization analysis revealed that the 2020 target won’t be achieved until 2026 at the earliest, six years late. Thus, the model suggested that a longer period may be needed to significantly reduce obesity in this population.

Different types of soluble fermentable dietary fibre decrease food intake, body weight gain and adiposity in young adult male rats.

BackgroundDietary fibre-induced satiety offers a physiological approach to body weight regulation, yet there is lack of scientific evidence. This experiment quantified food intake, body weight and body composition responses to three different soluble fermentable dietary fibres in an animal model and explored underlying mechanisms of satiety signalling and hindgut fermentation.MethodsYoung adult male rats were fed ad libitum purified control diet (CONT) containing 5% w/w cellulose (insoluble fibre), or diet containing 10% w/w cellulose (CELL), fructo-oligosaccharide (FOS), oat beta-glucan (GLUC) or apple pectin (PECT) (4 weeks; n = 10/group). Food intake, body weight, and body composition (MRI) were recorded, final blood samples analysed for gut satiety hormones, hindgut contents for fermentation products (including short-chain fatty acids, SCFA) and intestinal tissues for SCFA receptor gene expression.ResultsGLUC, FOS and PECT groups had, respectively, 10% (P < 0.05), 17% (P < 0.001) and 19% (P < 0.001) lower food intake and 37% (P < 0.01), 37% (P < 0.01) and 45% (P < 0.001) lower body weight gain than CONT during the four-week experiment. At the end they had 26% (P < 0.05), 35% (P < 0.01) and 42% (P < 0.001) less total body fat, respectively, while plasma total glucagon-like peptide-1 (GLP-1) was 2.2-, 3.2- and 2.6-fold higher (P < 0.001) and peptide tyrosine tyrosine (PYY) was 2.3-, 3.1- and 3.0-fold higher (P < 0.001). There were no differences in these parameters between CONT and CELL. Compared with CONT and CELL, caecal concentrations of fermentation products increased 1.4- to 2.2-fold in GLUC, FOS and PECT (P < 0.05) and colonic concentrations increased 1.9- to 2.5-fold in GLUC and FOS (P < 0.05), with no consistent changes in SCFA receptor gene expression detected.ConclusionsThis provides animal model evidence that sustained intake of three different soluble dietary fibres decreases food intake, weight gain and adiposity, increases circulating satiety hormones GLP-1 and PYY, and increases hindgut fermentation. The presence of soluble fermentable fibre appears to be more important than its source. The results suggest that dietary fibre-induced satiety is worthy of further investigation towards natural body weight regulation in humans.

Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity.

Melanocortin receptor accessory proteins (MRAPs) modulate signaling of melanocortin receptors in vitro. To investigate the physiological role of brain-expressed melanocortin 2 receptor accessory protein 2 (MRAP2), we characterized mice with whole-body and brain-specific targeted deletion of Mrap2, both of which develop severe obesity at a young age. Mrap2 interacts directly with melanocortin 4 receptor (Mc4r), a protein previously implicated in mammalian obesity, and it enhances Mc4r-mediated generation of the second messenger cyclic adenosine monophosphate, suggesting that alterations in Mc4r signaling may be one mechanism underlying the association between Mrap2 disruption and obesity. In a study of humans with severe, early-onset obesity, we found four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may also contribute to body weight regulation in humans.

Adaptive thermogenesis in human body weight regulation: more of a concept than a measurable entity?

According to Lavoisier, 'Life is combustion'. But to what extent humans adapt to changes in food intake through adaptive thermogenesis--by turning down the rate of heat production during energy deficit (so as to conserve energy) or turning it up during overnutrition (so as to dissipate excess calories)--has been one of the most controversial issues in nutritional sciences over the past 100 years. The debate nowadays is not whether adaptive thermogenesis exists or not, but rather about its quantitative importance in weight homoeostasis and its clinical relevance to the pathogenesis and management of obesity. Such uncertainties are likely to persist in the foreseeable future primarily because of limitations to unobtrusively measure changes in energy expenditure and body composition with high enough accuracy and precision, particularly when even small inter-individual variations in thermogenesis can, in dynamic systems and over the long term, be important in the determining weight maintenance in some and obesity and weight regain in others. This paper reviews the considerable body of evidence, albeit fragmentary, suggesting the existence of quantitatively important adaptive thermogenesis in several compartments of energy expenditure in response to altered food intake. It then discusses the various limitations that lead to over- or underestimations in its assessment, including definitional and semantics, technical and methodological, analytical and statistical. While the role of adaptive thermogenesis in human weight regulation is likely to remain more a concept than a strictly 'quantifiable' entity in the foreseeable future, the evolution of this concept continues to fuel exciting hypothesis-driven mechanistic research which contributes to advance knowledge in human metabolism and which is bound to result in improved strategies for the management of a healthy body weight.

Role of Sleep Timing in Caloric Intake and BMI

Sleep duration has been linked to obesity and there is also an emerging literature in animals demonstrating a relationship between the timing of feeding and weight regulation. However, there is a paucity of research evaluating timing of sleep and feeding on weight regulation in humans. The goal of this study was to evaluate the role of sleep timing in dietary patterns and BMI. Participants included 52 (25 females) volunteers who completed 7 days of wrist actigraphy and food logs. Fifty-six percent were "normal sleepers" (midpoint of <5:30 AM) and 44% were "late sleepers" (midpoint of sleep ≥5:30 AM). Late sleepers had shorter sleep duration, later sleep onset and sleep offset and meal times. Late sleepers consumed more calories at dinner and after 8:00 PM, had higher fast food, full-calorie soda and lower fruit and vegetable consumption. Higher BMI was associated with shorter sleep duration, later sleep timing, caloric consumption after 8:00 PM, and fast food meals. In multivariate models, sleep timing was independently associated with calories consumed after 8:00 PM and fruit and vegetable consumption but did not predict BMI after controlling for sleep duration. Calories consumed after 8:00 PM predicted BMI after controlling for sleep timing and duration. These findings indicate that caloric intake after 8:00 PM may increase the risk of obesity, independent of sleep timing and duration. Future studies should investigate the biological and social mechanisms linking timing of sleep and feeding in order to develop novel time-based interventions for weight management.

Chronobiological aspects of food intake and metabolism and their relevance on energy balance and weight regulation

Overweight and obesity are the result of a chronic positive energy balance, and therefore the only effective therapies are a diet which, on the long term, provides lower calories than the daily expended energy and exercise. Because nearly every physiological and biochemical function of the body shows circadian variations it can be suggested that also different chronobiological aspects of food intake, like time of day, meal frequency and regularity, and also circadian desynchronizations like in shift work may affect energy metabolism and weight regulation. The aim of this review is therefore to summarize and discuss studies that have addressed these issues in the past and to also provide an overview about circadian variations of selected aspects of metabolism, gut physiology and also factors that may influence overall energy regulation. The results show that a chronic desynchronization of the circadian system like in shift work and also sleep deprivation can favour the development of obesity. Also, regarding energy balance, a higher meal frequency and regular eating pattern seem to be more advantageous than taking the meals irregularly and seldom. Additional studies are required to conclude whether time of day-dependent food intake significantly influences weight regulation in humans.

The Energetics of Obesity: A Review: Monitoring Energy Intake and Energy Expenditure in Humans

Writing about obesity research is a challenging task. While the rising obesity epidemic drastically raised public awareness of the problem, the causes behind the epidemic are still poorly understood. The etiology of obesity is a subject of ongoing scientific debate with widely varying views and strong opinions. Is it mostly genetic or environmental in nature? Is obesity caused by changes in our diet or changes in lifestyle and physical activity or both? Modern research literature quite often offers conflicting findings. Publications in popular media like the one in Time magazine add to the controversy by making quick and strongly worded summaries of academic research. Although the root causes of obesity remains a topic of active research, this review concentrates on the fundamental components of weight regulation in humans and their relative contribution to the energy equation. A better understanding of the energetics of obesity may provide some insight into the etiology of the obesity epidemic. The energetics of obesity also showcases an engineering challenge: development of techniques to accurately measure individual components of the energy equation.

The Role of Leptin-Melanocortin System and Human Weight Regulation: Lessons from Experiments of Nature

Common obesity is a multi-factorial trait, contributed by the "obesogenic" environment of caloric abundance and increasing automation, sedentary lifestyle and an underlying genetic susceptibility. There have been major advances in the past decade in our understanding of the human weight regulation mechanism and pathogenesis of obesity, abetted by discoveries of genetic defects which lead to human obesity. Reports of genetic mutations causing obesity in humans and murine models were reviewed. Humans with genetic defects resulting in leptin deficiency, leptin receptor deficiency, proopiomelanocortin deficiency (POMC), and melanocortin 4 receptor (MC4R) deficiency developed severe obesity as the dominant phenotypic feature, though these are rare autosomal recessive conditions, except MC4R deficiency which is inherited in an autosomal co-dominant fashion. Common and rare variants of the POMC and melanocortin 3 receptor genes may be predisposing factors in the development of common obesity. Recent reports of human obesity associated with thyrosine kinase B (TrkB) defect and brain derived neurotrophic factor (BDNF) disruption, coupled with other murine studies, supported the role of BDNF/TrkB as effectors downstream of the melanocortin receptors. Despite exciting discoveries of single gene mutations resulting in human obesity, most cases of obesity are likely the result of subtle interactions of several related genetic variants with environmental factors which favour the net deposition of calories as fat, culminating in the obese phenotype. The mechanisms of action of these genes in the development of obesity are now being examined, with the aim of eventually discovering a therapeutic intervention for obesity.

The Role of Genes in the Current Obesity Epidemic

Obesity is a global pandemic and a major health concern. Obesity is a common but complex, multifactorial disorder with high heritability, where as much as 80% of the variance in the body mass index (BMI) is attributable to genetic factors. Literature on the contributing factors of the current obesity epidemic, and genetic basis of human obesity, were reviewed. The current increasing prevalence of obesity is a relatively recent global event driven by our modern lifestyle and dietary habits. Common obesity is the result of subtle interaction between numerous related genetic variants and environmental factors. The role of the obesity genes in this current epidemic is passive, but its impact is highly significant, because individuals with these genes may be predisposed to severe or even morbid obesity when exposed to the modern "obesogenic" environment. The human weight regulation mechanism evolved and becomes efficient in preventing weight loss, but is relatively ineffective in preventing excessive weight gain. The modern "obesogenic" environment encourages a sedentary lifestyle and provides easy access to processed food, which leads to a reduction of energy expenditure and increased caloric intake. We have inadvertently created a biology-environment mismatch, as the human weight regulation is unable to evolve fast enough to keep pace with the environmental change. This resulted in maladaptation of an otherwise sound and metabolically efficient physiological mechanism, with serious metabolic consequences.

Molecular physiology of weight regulation in mice and humans.

Evolutionary considerations relating to efficiency in reproduction, and survival in hostile environments, suggest that body energy stores are sensed and actively regulated, with stronger physiological and behavioral responses to loss than gain of stored energy. Many physiological studies support this inference, and suggest that a critical axis runs between body fat and the hypothalamus. The molecular cloning of leptin and its receptor-projects based explicitly on the search for elements in this axis-confirmed the existence of this axis and provided important tools with which to understand its molecular physiology. Demonstration of the importance of this soma-brain reciprocal connection in body weight regulation in humans has been pursued using both classical genetic approaches and studies of physiological responses to experimental weight perturbation. This paper reviews the history of the rationale and methodology of the cloning of leptin (Lep) and the leptin receptor (Lepr), and describes some of the clinical investigation characterizing this axis.

The Role of Melanocortin 3 Receptor Gene in Childhood Obesity

Melanocortin 3 receptor (MC3R) plays a critical role in weight regulation of rodents, but its role in humans remains unclear. The objective of this study was to identify genetic variants of the MC3R gene and determine its association with childhood obesity. We screened 201 obese children for MC3R gene mutations with anthropometric measurements, blood tests, feeding behavior, and body composition assessment. We identified three novel heterozygous mutations (Ile183Asn, Ala70Thr, and Met134Ile) in three unrelated subjects, which were not found in 188 control subjects, and two common polymorphisms Thr6Lys and Val81Ile. In vitro functional studies of the resultant mutant receptors revealed impaired signaling activity but normal ligand binding and cell surface expression. The heterozygotes demonstrated higher leptin levels and adiposity and less hunger compared with obese control subjects, reminiscent of the MC3R knockout mice. Family studies showed that these mutations may be associated with childhood or early-onset obesity. The common variants Thr6Lys and Val81Ile were in complete linkage disequilibrium, and in vitro studies revealed reduced signaling activity compared with wild-type MC3R. Obese subjects with the 6Lys/81Ile haplotype had significantly higher leptin levels, percentage body fat, and insulin sensitivity, and the causative role of the 6Lys/81Ile variants is supported by the presence of an additive effect in which heterozygotes had an intermediate phenotype compared with homozygotes. MC3R mutations may not result in autosomal dominant forms of obesity but may contribute as a predisposing factor to childhood obesity and exert an effect on the human phenotype. Our report supports the role of MC3R in human weight regulation.