The thrifty 'catch-up fat' phenotype: its impact on insulin sensitivity during growth trajectories to obesity and metabolic syndrome

The analyses of large epidemiological databases have suggested that infants and children who show catch-up growth, or adiposity rebound at a younger age, are predisposed to the development of obesity, type 2 diabetes and cardiovascular diseases later in life. The pathophysiological mechanisms by which these growth trajectories confer increased risks for these diseases are obscure, but there is compelling evidence that the dynamic process of catch-up growth per se, which often overlaps with adiposity rebound at a younger age, is characterized by hyperinsulinemia and by a disproportionately higher rate in the recovery of body fat than lean tissue (i.e. preferential 'catch-up fat'). This paper first focuses upon the almost ubiquitous nature of this preferential 'catch-up fat' phenotype across the life cycle as a risk factor for obesity and insulin-related complications - not only in infants and children who experienced catch-up growth after earlier fetal or neonatal growth retardation, or after preterm birth, but also in adults who show weight recovery after substantial weight loss owing to famine, disease-cachexia or periodic dieting. It subsequently reviews the evidence indicating that such preferential catch-up fat is primarily driven by energy conservation (thrifty) mechanisms operating via suppressed thermogenesis, with glucose thus spared from oxidation in skeletal muscle being directed towards de novo lipogenesis and storage in white adipose tissue. A molecular-physiological framework is presented which integrates emerging insights into the mechanisms by which this thrifty 'catch-up fat' phenotype crosslinks with early development of insulin and leptin resistance. In the complex interactions between genetic constitution of the individual, programming earlier in life, and a subsequent lifestyle of energy dense foods and low physical activity, this thrifty 'catch-up fat' phenotype--which probably evolved to increase survival capacity in a hunter-gatherer lifestyle of periodic food shortages--is a central event in growth trajectories to obesity and to diseases that cluster into the insulin resistance (metabolic) syndrome.     

Influence of catch-up growth on IGFBP-2 levels and association between IGFBP-2 and cardiovascular risk factors in Korean children born SGA

Small for gestational age (SGA) at birth and postnatal growth pattern may have an impact on insulin resistance and body composition in their later life. Emerging evidence has indicated that insulin-like growth factor binding protein-2 (IGFBP-2) may be related to insulin sensitivity. The aim of this study was to evaluate insulin resistance and IGFBP-2 levels in SGA children, and to identify the effect of catch-up growth on IGFBP-2 concentration. Serum IGFBP-2 levels were measured in 103 Korean SGA children including 49 prepubertal and 54 pubertal subjects. Anthropometric values, fasting serum levels of metabolic parameters and insulin sensitivity indices were determined. Each prepubertal or pubertal group was subgrouped based on height or weight catch-up growth. The subgroups with weight catch-up showed higher values of BMI, body fat mass, percent body fat, and total cholesterol. Particularly in pubertal children, IGFBP-2 concentration was lower in the subgroup with weight catch-up. Catch-up growth in height did not affect insulin resistance and metabolic parameters. IGFBP-2 levels were inversely correlated with BMI, body fat mass, percent body fat, insulin and leptin levels in both prepubertal and pubertal groups. Additionally in the pubertal group, systolic blood pressure, cholesterol levels were related to IGFBP-2. A strong relationship between IGFBP-2, the insulin sensitivity index, and some cardiovascular risk factors was observed in children born SGA, suggesting that IGFBP-2 might be a promising marker for early recognition of insulin resistance, particularly in children with weight catch-up.     

Thrifty energy metabolism in catch-up growth trajectories to insulin and leptin resistance

Catch-up growth early in life (after fetal, neonatal or infantile growth retardation) is a major risk factor for later obesity, type-2 diabetes and cardiovascular diseases. These risks are generally interpreted alongside teleological arguments that environmental exposures which hinder growth early in life lead to programming of 'thrifty mechanisms' that are adaptive during the period of limited nutrient supply (or growth constraint), but which increase risks for diseases during improved nutrition and catch-up growth later in life. This paper addresses this notion of 'thrifty mechanisms' in the light of evidence that catch-up growth is characterized by a disproportionately higher rate of fat gain relative to lean tissue gain, and that such preferential catch-up fat is in part driven by energy conservation mechanisms operating via suppressed thermogenesis. It provides a molecular-physiological framework which integrates emerging insights into mechanisms by which this thrifty 'catch-up fat' phenotype cross-links with insulin and leptin resistance.     

Fetal programming: prenatal testosterone excess leads to fetal growth retardation and postnatal catch-up growth in sheep

Alterations in the maternal endocrine, nutritional, and metabolic environment disrupt the developmental trajectory of the fetus, leading to adult diseases. Female offspring of rats, subhuman primates, and sheep treated prenatally with testosterone (T) develop reproductive/metabolic defects during adult life similar to those that occur after intrauterine growth retardation. In the present study we determined whether prenatal T treatment produces growth-retarded offspring. Cottonseed oil or T propionate (100 mg, im) was administered twice weekly to pregnant sheep between 30-90 d gestation (term = 147 d; cottonseed oil, n = 16; prenatal T, n = 32). Newborn weight and body dimensions were measured the day after birth, and postnatal weight gain was monitored for 4 months in all females and in a subset of males. Consistent with its action, prenatal T treatment produced females and males with greater anogenital distances relative to controls. Prenatal T treatment reduced body weights and heights of newborns from both sexes and chest circumference of females. Prenatally T-treated females, but not males, exhibited catch-up growth during 2-4 months of postnatal life. Plasma IGF-binding protein-1 and IGF-binding protein-2, but not IGF-I, levels of prenatally T-treated females were elevated in the first month of life, a period when the prenatally T-treated females were not exhibiting catch-up growth. This is suggestive of reduced IGF availability and potential contribution to growth retardation. These findings support the concept that fetal growth retardation and postnatal catch-up growth, early markers of future adult diseases, can also be programmed by prenatal exposure to excess sex steroids.     

Adiposity in children born small for gestational age

Epidemiological studies indicate that children born small for gestational age (SGA) have an increased risk of metabolic and cardiovascular disorders as adults. This suggests that foetal undernutrition leads to permanent metabolic alterations, which predispose to metabolic abnormalities upon exposure to environmental factors such as low physical activity and/or high-energy intake in later life (thrifty phenotype hypothesis). However, this relationship is not restricted to foetal undernutrition or intrauterine growth retardation, but is also found for children born premature, or for high birth weight children. Furthermore, early post-natal nutrition, and more specifically catch-up growth, appear to modulate cardiovascular risk as well. Intrauterine growth retardation can be induced in animal models by energy/protein restriction, or ligation of uterine arteries. In such models, altered glucose homeostasis, including low beta-cell mass, low insulin secretion and insulin resistance is observed after a few weeks of age. In humans, several studies have confirmed that children born SGA have insulin resistance as adolescents and young adults. Alterations of glucose homeostasis and increased lipid oxidation can indeed be observed already in non-diabetic children born SGA at early pubertal stages. These children also have alterations of stature and changes in body composition (increased fat mass), which may contribute to the pathogenesis of insulin resistance. Permanent metabolic changes induced by foetal/early neonatal nutrition (metabolic inprinting) may involve modulation of gene expression through DNA methylation, or alterations of organ structure. It is also possible that events occurring during foetal/neonatal development lead to long-lasting alterations of the hypothalamo-pituitary-adrenal axis or the hypothalamo-pituitary-insulin-like growth factor-1 axis.     

Small for gestational age: short stature and beyond

Depending on the definitions used, up to 10% of all live-born neonates are small for gestational age (SGA). Although the vast majority of these children show catch-up growth by 2 yr of age, one in 10 does not. It is increasingly recognized that those who are born SGA are at risk of developing metabolic disease later in life. Reduced fetal growth has been shown to be associated with an increased risk of insulin resistance, obesity, cardiovascular disease, and type 2 diabetes mellitus. The majority of pathology is seen in adults who show spontaneous catch-up growth as children. There is evidence to suggest that some of the metabolic consequences of intrauterine growth retardation in children born SGA can be mitigated by ensuring early appropriate catch-up growth, while avoiding excessive weight gain. Implicitly, this argument questions current infant formula feeding practices. The risk is less clear for individuals who do not show catch-up growth and who are treated with GH for short stature. Recent data, however, suggest that long-term treatment with GH does not increase the risk of type 2 diabetes mellitus and the metabolic syndrome in young adults born SGA.     

Growth hormone during catch-up growth and failure of catch-up growth in rats.

Male Long-Evans rats were fasted or given cortisone injections beginning at 37 days of age in order to produce growth retardation. They were then allowed to recover for periods of up to 28 days. GH concentration was measured in trunk blood plasma of rats decapitated after minimal stress. During the recovery period there was a significant increase in plasma GH in both experimental groups. Organ weight/body weight ratios for liver and heart, protein/tissue, DNA/tissue, and DNA/protein ratios of liver, heart, and skeletal muscle were found to remain normal or to return to normal values during the recovery periods in both experimental groups. DNA content was reduced in both liver and heart at 14 days. At later recovery periods no significant differences from controls were observed. The findings indicate that increased GH release is common to the growth recovery period after both fasting or cortisone treatment. GH concentration in plasma does not correlate with presence or absence of catch-up growth. The organ weight/body weight ratios correlate with previous findings showing prompt return to normal proportions of body weight to tail length in both the cortisone and fast models irrespective of presence or absence of catch-up growth. The results indicate that failure of catch-up growth after cortisone treatment is not the result of decreased pituitary GH secretion. It is probable that multiple factors working in concert are responsible for recovery after transient growth retardation.     

Body composition phenotypes in pathways to obesity and the metabolic syndrome

Dynamic changes in body weight have long been recognized as important indicators of risk for debilitating diseases. While weight loss or impaired growth can lead to muscle wastage, as well as to susceptibility to infections and organ dysfunctions, the development of excess fat predisposes to type 2 diabetes and cardiovascular diseases, with insulin resistance as a central feature of the disease entities of the metabolic syndrome. Although widely used as the phenotypic expression of adiposity in population and gene-search studies, body mass index (BMI), that is, weight/height(2) (H(2)), which was developed as an operational definition for classifying both obesity and malnutrition, has considerable limitations in delineating fat mass (FM) from fat-free mass (FFM), in particular at the individual level. After an examination of these limitations within the constraints of the BMI-FM% relationship, this paper reviews recent advances in concepts about health risks related to body composition phenotypes, which center upon (i) the partitioning of BMI into an FM index (FM/H(2)) and an FFM index (FFM/H(2)), (ii) the partitioning of FFM into organ mass and skeletal muscle mass, (iii) the anatomical partitioning of FM into hazardous fat and protective fat and (iv) the interplay between adipose tissue expandability and ectopic fat deposition within or around organs/tissues that constitute the lean body mass. These concepts about body composition phenotypes and health risks are reviewed in the light of race/ethnic variability in metabolic susceptibility to obesity and the metabolic syndrome.     

Menopausal obesity and metabolic syndrome - PolSenior study

Obesity is a common problem and its health consequences depend on the phenotype of obesity. Clinical aspects of three phenotypes of obesity: upper body (visceral), lower body (healthy) and metabolic obesity with normal weight are discussed. The PolSenior study and other data show that the incidence of obesity increases during hormonal climacteric transformation with special emphasis on visceral (72%) and metabolic obesity with normal weight (16%). The etiology of menopausal obesity and fat redistribution with an increase incidence of menopausal metabolic syndrome is presented. The role of sex hormones and SHBG of fat mass and fat distribution in postmenopausal women is discussed on the basis of PolSenior study. The diagnostic-therapeutic algorithm for climacteric women is recommended according to cardiovascular diseases risk (CVD), elevated waist circumference, serum triglicerides, decreased HDL cholesterol, elevated fasting glucose, HOMA over 1.69 and BP over 130/80 mmHg. In women with CVD risk factors the metformin therapy is a golden standard.     

Clinical spectrum of premature pubarche: Links to metabolic syndrome and ovarian hyperandrogenism

Premature pubarche—defined as the appearance of pubic hair before age 8 years in girls and 9 years in boys—has been traditionally considered a benign entity. However, recent evidence supports the notion that premature pubarche in girls may be a forerunner of the metabolic syndrome, and may precede the development of clinical ovarian androgen excess in adolescence. This sequence seems to occur more frequently when premature pubarche was preceded by reduced fetal growth and followed by excessive postnatal catch-up in height and particularly in weight; hyperinsulinemia appears to be a key factor in the development of this sequence of events. In girls with premature pubarche and a history of a low birth weight, puberty tends to start earlier and to have a faster course, so that final height may be moderately reduced. In these girls, metformin therapy may reverse the progression to clinical ovarian hyperandrogenism, normalize body composition and excess visceral fat, and delay pubertal progression without attenuating linear growth and bone mineralization, suggesting that adult height may be improved. Long-term follow-up of these patients is needed to fully determine the ultimate effects of insulin sensitization as well as the maintenance of these benefits after discontinuation of therapy.     

Leptin-independent programming of adult body weight and adiposity in mice

Low birth weight and rapid postnatal weight gain are independent and additive risk factors for the subsequent development of metabolic disease. Despite an abundance of evidence for these associations, mechanistic data are lacking. The hormone leptin has received significant interest as a potential programming factor, because differences in the profile of leptin in early life have been associated with altered susceptibility to obesity. Whether leptin alone is a critical factor for programming obesity has, until now, remained unclear. Using the leptin-deficient ob/ob mouse, we show that low birth weight followed by rapid catch-up growth during lactation (recuperated offspring) leads to a persistent increase in body weight in adult life, both in wild-type and ob/ob animals. Furthermore, recuperated offspring are hyperphagic and epididymal fat pad weights are significantly increased, reflecting greater adiposity. These results show definitively that factors other than leptin are crucial in the programming of energy homeostasis in this model and are powerful enough to alter adiposity in a genetically obese strain.     

早期营养干预对宫内生长迟缓大鼠瘦素、胰岛素敏感性的影响

目的　探寻既能保证宫内生长迟缓 (IUGR )大鼠生长追赶又可避免或减轻其在成年期产生胰岛素抵抗 (IR)的早期营养干预措施。方法　用孕鼠全程饥饿法建立IUGR大鼠模型。IUGR新生雌鼠60只随机分为五组 :( 1)IUGR对照组给予常规饲料 ;( 2 )高碳水化合物组 ;( 3 )高脂肪组 ;( 4 )高蛋白质组 ;( 5 )低蛋白质组。正常新生雌鼠 12只为正常对照组。幼鼠在 3周喂乳期间母鼠分别摄食上述饲料 ,第 4周起各组幼鼠均以常规饲料饲养。各组新生鼠于第 4周、12周分别测定体重、肾周脂肪重量、血清瘦素、血糖、胰岛素并计算胰岛素敏感指数 (ISI)。结果　IUGR高蛋白质组在 4周呈现不伴肾周脂肪增加的体重追赶生长 ,在 12周肾周脂肪不增多 ,瘦素、ISI均与正常对照组比较差异无显著性 ,不出现IR。结论　生后哺乳期高蛋白饮食继后恢复正常饮食是早期营养干预IUGR的合理措施。 12周时血清瘦素水平可作为观察IUGR大鼠成年后发生IR的一个生化指标。     

Metabolic implications of GH treatment in small for gestational age

Fetal growth retardation is associated with decreased postnatal growth, resulting in a lower adult height. In addition, a low birth weight is associated with an increased risk of developing diseases during adulthood, such as insulin resistance, type 2 diabetes mellitus, hypertension, dyslipidemia, and cardiovascular diseases. Children with persistent postnatal growth retardation, i.e., incomplete catch-up growth, can be treated with human GH. The GH/IGF-I axis is involved in the regulation of carbohydrate and lipid metabolism. The question of whether treatment with GH in children born small for gestational age (SGA) has long-term implications with respect to glucose/insulin and lipid metabolism has not been answered yet. In this article, the available data are reviewed.     

Obesity: a disease or a biological adaptation?

The increase in obesity prevalence is problematic as this condition is associated with health complications such as diabetes and cardiovascular diseases, more particularly when the excess body fat is stored in the deep abdominal region. On the other hand, obesity facilitates the maintenance of body homeostasis probably because of an increased hormonal gradient which favours the regulation of energy balance, to give but one example. The regulation potential of excess body fat is particularly apparent in the reduced‐obese state where a reduction of energy expenditure, fat oxidation and some immune system markers, as well as an increase in appetite, stress vulnerability and circulating and adipose tissue organochlorines have been observed. These constitute another category of risk factors which can certainly favour the accumulation of body fat to reestablish body homeostasis on other fronts. Under such conditions, obesity is perceived by the physiologist as a necessary biological adaptation rather than a disease. For health professionals, this emphasizes the importance to seek a reasonable compromise between the favourable reduction of risk to develop metabolic complications by body weight loss and the physiological vulnerability which is also generated by such an intervention.     

Early childhood predictors of adult body composition

Intra-uterine life has been identified as a possible critical period for the development of obesity risk in both adults and children; others have highlighted the importance of growth and nutrition in the first few years. It is suggested that fetal growth, as assessed by birth weight, may programme lean body mass later in life. Children who are born small for gestational age also have a predisposition to accumulating fat mass, particularly intra-abdominal fat. It is not yet clear whether this predisposition is due to their prenatal growth restraint, their rapid postnatal catch-up growth or a combination of both. Recently, genetic and heritable factors have been shown to contribute to both rapid postnatal growth and childhood obesity risk in children and adults. Future studies should explore their timing of action and potential interactions with markers of antenatal growth restraint.     

Resistance training,visceral obesity and inflammatory response: a review of the evidence

Intra‐abdominal obesity is an important risk factor for low‐grade inflammation, which is associated with increased risk for diabetes mellitus and cardiovascular disease. For the most part, recommendations to treat or prevent overweight and obesity via physical activity have focused on aerobic endurance training as it is clear that aerobic training is associated with much greater energy expenditure during the exercise session than resistance training. However, due to the metabolic consequences of reduced muscle mass, it is understood that normal ageing and/or decreased physical activity may lead to a higher prevalence of metabolic disorders. Whether resistance training alters visceral fat and the levels of several pro‐inflammatory cytokines produced in adipose tissue has not been addressed in earlier reviews. Because evidence suggests that resistance training may promote a negative energy balance and may change body fat distribution, it is possible that an increase in muscle mass after resistance training may be a key mediator leading to a better metabolic control. Considering the benefits of resistance training on visceral fat and inflammatory response, an important question is: how much resistance training is needed to confer such benefits? Therefore, the purpose of this review was to address the importance of resistance training on abdominal obesity, visceral fat and inflammatory response.     

Reductions in caloric intake and early postnatal growth prevent glucose intolerance and obesity associated with low birthweight

Aims/hypothesis Low birthweight (LBW) and rapid postnatal weight gain, or catch-up growth, are independent risk factors for the development of obesity and diabetes during adult life. Individuals who are both small at birth and have postnatal catch-up growth are at the highest risk. We hypothesised that dietary interventions designed to attenuate catch-up growth in LBW subjects may have long-term beneficial consequences.Materials and methods We used our previously described mouse model of LBW-associated diabetes, created by restricting maternal food intake to 50% during the last week of gestation. Control (C) dams and dams that had been subjected to undernutrition (U) were then provided either chow ad libitum after delivery or 50% food restriction on a per-day basis from delivery until weaning. We designated the resulting four groups control-control (CC), undernutrition-control (UC), control-undernutriton (CU) and undernutrition-undernutrition (UU), indicating the prenatal and postnatal experimental conditions, respectively. Carbohydrate metabolism and adiposity were assessed prospectively in offspring until age 6 months.Results Males that were small at birth and exhibited early postnatal catch-up growth developed glucose intolerance and obesity by age 6 months. In contrast, LBW mice without catch-up growth (UU) remained smaller than controls (CC), and glucose intolerance and obesity was prevented. Similarly, mice with normal birthweight that had blunted catch-up growth (CU) were leaner and had better tolerance test than CC mice. Catch-up growth during the first week of life correlated better than birthweight with glucose, fat mass and glucose tolerance up to 6 months of age.Conclusions/interpretation Prevention of early catch-up growth reversed the development of glucose intolerance and obesity in our mouse model of LBW-associated diabetes.     

Epigenetic regulation and fetal programming

Fetal programming encompasses the role of developmental plasticity in response to environmental and nutritional signals during early life and its potential adverse consequences (risk of cardiovascular, metabolic and behavioural diseases) in later life. The first studies in this field highlighted an association between poor fetal growth and chronic adult diseases. However, environmental signals during early life may lead to adverse long-term effects independently of obvious effects on fetal growth. Adverse long-term effects reflect a mismatch between early (fetal and neonatal) environmental conditions and the conditions that the individual will confront later in life. The mechanisms underlying this risk remain unclear. However, experimental data in rodents and recent observations in humans suggest that epigenetic changes in regulatory genes and growth-related genes play a significant role in fetal programming. Improvements in our understanding of the biochemical and molecular mechanisms at play in fetal programming would make it possible to identify biomarkers for detecting infants at high risk of adult-onset diseases. Such improvements should also lead to the development of preventive and therapeutic strategies.     

Decrease in visceral fat following diet-induced weight loss in upper body compared to lower body obese premenopausal women

BACKGROUND: Obesity is associated with numerous metabolic disturbances, such as insulin resistance, diabetes mellitus type 2, dyslipidemia, and hypertension. An excess of fat within the abdomen, so-called visceral adiposity, confers a greater and independent health risk of metabolic and cardiovascular complications than does adipose tissue accumulation elsewhere. The present study aimed to investigate a possible differential effect of diet-induced weight loss in visceral fat mass and metabolic parameters in obese individuals with the upper body (UBO) and lower body (LBO) obese phenotype. METHODS: The obese subjects were prescribed a liquid, very-low calorie diet to reduce 50% of their overweight (15% body weight loss). Specific body fat measurements (MRI, BIA), anthropometrics, and fasting metabolic parameters were obtained in control subjects and two groups of obese subjects (UBO and LBO) before and after weight loss. RESULTS: Weight loss was accompanied by significant decreases in total, subcutaneous, and visceral fat in both UBO and LBO women. The largest reduction in visceral fat mass was found in the UBO women (absolute decrease 223+/-32 cm(2) vs 122+/-91 cm(2) in LBO women; P=0.01), while the amount of visceral fat was reduced to normal levels in LBO women (155+/-25 cm(2) after weight loss vs 143+/-17 cm(2) in controls; P=NS). Furthermore, weight loss significantly lowered fasting glucose, total cholesterol, and LDL cholesterol concentrations in UBO women. CONCLUSION: The obese phenotype is preserved after body weight loss. UBO women have to lose a larger amount of overweight in order to bring the amount of fat in the visceral depot down to normal levels and to obtain normalization of their cardiovascular risk profile.     

重视肥胖的心血管危险及其适当干预

肥胖已成为我国心血管病患病率升高的主要危险因素,应用影像学技术有助于诊断内脏脂肪型肥胖。虽然大量研究证实肥胖与心血管疾病的患病率高度相关,但心血管疾病的预后则与肥胖程度存在矛盾现象,体重指数或脂肪比例过高或过低均增加死亡风险。脂肪的功能和类型决定其对心血管的效应及转归,保持合适的体重指数和脂肪比例对心血管有保护作用。肥胖的干预目标,除减肥及降低远期心血管事件外,尚需改善脂肪本身的病变。