The Development of Obesity Begins at an Early Age in Captive Common Marmosets (Callithrix jacchus)

Animal models to study the causes and consequences of obesity during infancy in humans would be valuable. In this study, we examine the patterns of fat mass gain from birth to 12 months in common marmosets (Callithrix jacchus). Lean and fat mass was measured by quantitative magnetic resonance at 1, 2, 6, and 12 months for 31 marmosets, 15 considered Normal and 16 considered Fat (>14% body fat) at 12 months. Animals were fed either the regular colony diet mix or a high‐fat variation. Subjects classified as Fat at 12 months already had greater lean mass (198.4 ± 6.2 g vs. 174.0 ± 6.8 g, P = 0.013) and fat mass (45.5 ± 5.0 g vs. 24.9 ± 3.4 g, P = .002) by 6 months. Body mass did not differ between groups prior to 6 months, however, by 1 month, Fat infants had greater percent body fat. Percent body fat decreased between 1 and 12 months in Normal subjects; in Fat subjects, it increased. The high‐fat diet was associated with body fat >14% at 6 months (P = 0.049), but not at 12 months. This shift was due to three subjects on the normal diet changing from Normal to Fat between 6 and 12 months. Although maternal prepregnancy adiposity did not differ, overall, between Normal and Fat subjects, the subjects Normal at 6 and Fat at 12 months all had Fat mothers. Therefore, diet and maternal obesity appear to have potentially independent effects that may also vary with developmental age. Although birth weight did not differ between groups, it was associated with fat mass gain from 1 to 6 months in animals with >14% body fat at 6 months of age (r = 0.612, P = 0.026); but not in 6‐month‐old animals with <14% body fat (r = –0.012, P = 0.964). Excess adiposity in captive marmosets develops by 1 month. Birth weight is associated with adiposity in animals vulnerable to obesity.     

Gender differences between hypocretin/orexin knockout and wild type mice: age,body weight,body composition,metabolic markers,leptin and insulin resistance

Female hypocretin knockout (Hcrt KO) mice have increased body weight despite decreased food intake compared to wild type (WT) mice. In order to understand the nature of the increased body weight, we carried out a detailed study of Hcrt KO and WT, male, and female mice. Female KO mice showed consistently higher body weight than WT mice, from 4 to 20 months (20–60%). Fat, muscle, and free fluid levels were all significantly higher in adult (7–9 months) as well as old (18–20 months) female KO mice compared to age‐matched WT mice. Old male KO mice showed significantly higher fat content (150%) compared to age‐matched WT mice, but no significant change in body weight. Respiratory quotient (?19%) and metabolic rates (?14%) were significantly lower in KO mice compared to WT mice, regardless of gender or age. Female KO mice had significantly higher serum leptin levels (191%) than WT mice at 18–20 months, but no difference between male mice were observed. Conversely, insulin resistance was significantly higher in both male (73%) and female (93%) KO mice compared to age‐ and sex‐matched WT mice. We conclude that absence of the Hcrt peptide has gender‐specific effects. In contrast, Hcrt‐ataxin mice and human narcoleptics, with loss of the whole Hcrt cell, show weight gain in both sexes.

     

Fetal Origins of Obesity

The worldwide epidemic of obesity continues unabated. Obesity is notoriously difficult to treat, and, thus, prevention is critical. A new paradigm for prevention, which evolved from the notion that environmental factors in utero may influence lifelong health, has emerged in recent years. A large number of epidemiological studies have demonstrated a direct relationship between birth weight and BMI attained in later life. Although the data are limited by lack of information on potential confounders, these associations seem robust. Possible mechanisms include lasting changes in proportions of fat and lean body mass, central nervous system appetite control, and pancreatic structure and function. Additionally, lower birth weight seems to be associated with later risk for central obesity, which also confers increased cardiovascular risk. This association may be mediated through changes in the hypothalamic pituitary axis, insulin secretion and sensing, and vascular responsiveness. The combination of lower birth weight and higher attained BMI is most strongly associated with later disease risk. We are faced with the seeming paradox of increased adiposity at both ends of the birth weight spectrum—higher BMI with higher birth weight and increased central obesity with lower birth weight. Future research on molecular genetics, intrauterine growth, growth trajectories after birth, and relationships of fat and lean mass will elucidate relationships between early life experiences and later body proportions. Prevention of obesity starting in childhood is critical and can have lifelong, perhaps multigenerational, impact.     

Effects of Growth Hormone Administration in Human Obesity

Objective: To summarize the reports in the literature regarding the effect of growth hormone (GH) treatment of obesity. Research Methods and Procedures: Clinical trials of GH treatment of obese adults were reviewed and summarized. Specifically, information regarding the effects of GH on body fat and body fat distribution, glucose tolerance/insulin resistance, and adverse consequences of treatment were recorded. Results: GH administered together with hypocaloric diets did not enhance fat loss or preserve lean tissue mass. No studies provided strong evidence for an independent beneficial effect of GH on visceral adiposity. In all but one study, glucose tolerance during GH treatment suffered relative to placebo. Conclusion: The bulk of studies indicate little or no beneficial effects of GH treatment of obesity despite the low serum GH concentrations associated with obesity.     

Body composition of obese subjects by air displacement plethysmography: The influence of hydration

Objective: We investigated whether air displacement plethysmography (ADP) could detect small changes in body composition of obese subjects with alterations in hydration. Research Methods and Procedures: Ten obese subjects (mean BMI, 39.3 ± 2.8 kg/m²) entered the ADP chamber without and with oil (1, 2, or 4 liters), water (1, 2, or 4 liters), or mixed (1 liter oil + 1 liter water or 2 liters oil + 2 liters water) loads. Real and measured changes in body composition were compared by regression analysis and Bland‐Altman procedures. Results: The ADP‐measured changes in volume did not differ from the real values and were strongly correlated with them (r = 0.98). In all cases, loads of differing composition and similar volume led to different values of fat, fat‐free mass, and percentage fat. Water was detected as increased fat‐free mass only with loads of ≥2 liters, most of the water being falsely detected as increased fat mass. The observed changes were correlated with the real ones for fat mass (r = 0.68; p < 0.0001), fat‐free mass (r = 0.66; p < 0.0001), and percentage fat (r = 0.61; p < 0.0001), but fat mass changes were overestimated by ～1 kg, and fat‐free mass changes were underestimated by ～1 kg. This underestimation increased with the highest water loads, as shown by the Bland‐Altman plot (r = ?0.27; p < 0.05). Percentage fat changes were overestimated by 0.8% (p < 0.001); the magnitude of the error was correlated with the weight of the water load (r = 0.62; p < 0.0001). Discussion: ADP accurately measures changes in body volume, discriminating small changes in body composition. It overestimates changes in adiposity, as most of the increased hydration is detected as an enlarged fat mass.     

The Case for Medical Management of Obesity: A Call for Increased Physician Involvement

The United States is in the midst of an escalating epidemic of obesity. Over one-third of the adult population in the United States is currently obese and the prevalence of obesity is growing rapidly. By any criteria, obesity represents a chronic disease which is associated with a wide range of comorbidities, including coronary heart disease (CHD), Type 2 diabetes, hypertension and dyslipidemias. The comorbidities of obesity are common, occurring in over 70% of individuals with a BMI of ≥ 27. In addition to obesity itself, excessive accumulation of visceral abdominal fat and significant adult weight gain also represent health risks. Physicians have an important role to play in the treatment of obesity. Unfortunately, the medical community has not been involved actively enough to help stem the major epidemic of obesity occurring in the United States. This article puts forth a proposed model for the treatment of obesity in clinical practice, including obtaining the “vital signs” of obesity, recommending lifestyle measures, and instituting pharmacologic therapy when appropriate. By utilizing a chronic disease treatment model, physicians can join other health care professionals to effectively treat the chronic disease of obesity. Relatively modest weight loss, on the order of 510% of initial body weight can result in significant health improvements for many patients and represent an achievable goal for most obese patients.     

Antiobesity Effects of Bifidobacterium breve Strain B-3 Supplementation in a Mouse Model with High-Fat Diet-Induced Obesity

The aim of the present study was to evaluate the anti-obesity activity of a probiotic bifidobacterial strain in a mouse model with obesity induced by a high-fat diet. The mice were fed a high-fat diet supplemented with Bifidobacterium breve B-3 at 10⁸ or 10⁹ CFU/d for 8 weeks. B. breve B-3 supplementation dose-dependently suppressed the accumulation of body weight and epididymal fat, and improved the serum levels of total cholesterol, fasting glucose and insulin. The bifidobacterial counts in the caecal contents and feces were significantly increased with the B. breve B-3 administration. The expression of genes related to fat metabolism and insulin sensitivity in the gut and epididymal fat tissue was up-regulated by this administration. These results suggest that the use of B. breve B-3 would be effective in reducing the risk of obesity.     

The Canadian Obesity Epidemic: An Historical Perspective

Objective: To examine temporal trends in stature, body mass, body mass index (BMI), and the prevalence of overweight and obesity in Canada. Research Methods and Procedures: Data for adults 20 to 64 years of age were compared across eight Canadian surveys conducted between 1953 and 1998. Temporal trends in stature and body mass were examined using regression, and changes in weight‐for‐height were expressed as changes from 1953. BMI data were available from 1970 to 1972 to examine changes in overweight and obesity. Qualitative changes in the BMI distribution were examined using Tukey mean‐difference plots. Results: Significant temporal trends in stature and body mass have occurred since 1953 in Canada. Median stature increased 1.4 cm/decade in men and 1.1 cm/decade in women, whereas median body mass increased 1.9 kg/decade in men and 0.8 kg/decade in women. Increases in the 75th percentile of body mass were larger than the median. The average weight‐for‐height increased 5.1% in men and 4.9% in women from 1953. Furthermore, the prevalences of overweight and obesity have increased from 40.0% and 9.7% in 1970–1972 to 50.7% and 14.9% in 1998, respectively. The entire BMI distribution has shifted to the right since 1970–1972 and has become more skewed to the right for men than for women. Discussion: There have been significant increases in stature and body mass in Canada over the last 45 years. Body mass has increased more than stature, particularly in the upper percentiles, which has resulted in the currently observed high prevalences of overweight and obesity.     

Relation of the White Blood Cell Count to Obesity and Insulin Resistance: Effect of Race and Gender

PRATLEY, RICHARD E, CHARLTON WILSON AND CLIFTON BOGARDUS. Relation of the white blood cell count to obesity and insulin resistance: effect of race and gender. Obes Res. Recent reports suggest that the white blood cell (WBC) count is related to plasma insulin concentrations and insulin resistance in healthy individuals. The present study examines whether these relations are independent of obesity and the pattern of body fat distribution and tests whether race and gender affect these relations. WBC counts, insulin responses to a 75 gram oral glucose tolerance test (OGTT) and glucose disposal during a two-step hyperinsulinemic euglycemic clamp were measured in 300 men and women (149 Pima Indians, 100 whites, and 51 blacks) with a wide range of obesity. WBC counts were lower in blacks than Pima Indians or whites and tended to be higher in women than men. The subgroups were comparable in age and body weight, but percent body fat and plasma insulin concentrations were higher and glucose disposal during the glucose clamp was lower in Pima Indians than in blacks or whites. In the group as a whole, the WBC count correlated with obesity (body mass index and percent body fat), the waist to thigh ratio (an index of the pattern of body fat distribution), and plasma insulin concentrations and was negatively related to age and glucose disposal during the clamp. In multiple regression analyses, only age, race and obesity were significantly associated with the WBC count. When the analyses were restricted to Pima men, in whom correlations between the WBC count and the metabolic variables appeared the strongest, the WBC count remained significantly associated with plasma insulin concentrations, but not glucose disposal, after controlling for age and obesity. The results of this study indicate that age, race, and obesity are significantly associated with the WBC count in healthy individuals. Plasma insulin concentrations, but not insulin resistance per se, may also be weakly associated with the WBC count, but this may be population specific.     

Brain Peptides and Obesity: Pharmacologic Treatment

Obesity results from an imbalance between nutrient ingestion and metabolism, with more calories being ingested than utilized. The brain plays an important role in coordinating these complex behavioral and physiological functions, operating through multiple neurochemical systems with distinct properties. This review focuses on two hypothalamic peptide systems, neuropeptide Y (NPY) and galanin (GAL), that illustrate how the brain operates through different mechanisms to control the body's nutrient stores, in different states or conditions. These peptides have different behavioral and physiological effects and are, themselves, differentially responsive to feedback signals from circulating steroids, peptides, and nutrients. They can be distinguished by their relation to natural feeding patterns and endogenous hormones and by their specificity of action in relation to natural biological rhythms. The neuroanatomical substrates involved in these actions of NPY and GAL are also distinct. The neurocircuit mediating NPY's actions originates in the arcuate nucleus and terminates in the medial portion of the paraventricular nucleus; the GAL-containing neurons, in contrast, are concentrated in the lateral portion of the paraventricular nucleus, in addition to the medial preoptic area, which contribute to local GAL innervation as well as projections to the median eminence. Regarding their distinct functions, the evidence suggests that the NPY system is more closely related to patterns of carbohydrate ingestion and carbohydrate utilization, channeling nutrients towards the synthesis of fat. It is most strongly activated at the start of the active feeding cycle or after weaning, in close association with the adrenal steroid, corticosterone. The GAL system, in contrast, is more closely associated with patterns of fat consumption and signals related to fat oxidation. This peptide system is most active during the middle of the feeding cycle or immediately after puberty, in close association with the gonadal steroids. The gene expression and synthesis of these peptides in their respective neuronal cell groups is inhibited by circulating insulin and altered by dietary nutrients. Disturbances in sensitivity to insulin and steroid feedback regulation in the brain are believed to be involved in producing abnormal patterns of peptide function that result in overeating and body weight gain.     

Insulin Normalization as an Approach to the Pharmacological Treatment of Obesity

Hyperinsulinemia and exaggerated insulin response to glucose are among the hallmarks of obesity. However, the role of hyperinsulinemia in the etiology and maintenance of obesity has been controversial. If hyperinsulinemia plays a critical role as proposed, then its reversal may have therapeutic potential. To test this hypothesis, the activity of Ro 23–7637, {4-(2,2-diphenylethenyl)-1-[1-oxo-9-(3-pyridinyl) nonyl]piperidine}, which partially normalizes plasma insulin by an action on pancreatic islets from obese rats, was assessed. When islets were cultured for 2 days with 10 μM Ro 23–7637, a significant reduction in the exaggerated glucose-induced insulin secretion was observed. When islets from lean rats were exposed to Ro 23–7637, no reduction in insulin secretion was observed. The effects of oral administration of Ro 23–7637 were assessed in Zucker and diet-induced obese rats in doses ranging from 5 to 90 mg/kg/day. Dose-related reductions were observed in: 1) glucose-induced insulin secretion; 2) basal insulin concentration; 3) daily food intake; and 4) body weight gain. In diet-induced obese rats, selective mobilization of fat, maintenance of body protein, and decreased energetic efficiency were also observed. An association between the partial normalization of glucose-induced insulin responses and reductions of basal insulin, reduced rates of body weight gain or body weight loss and decreased food intake was observed in obese rats. Therefore, these studies indicate that Ro 23–7637 is an orally active, efficacious antiobesity agent.     

The Yellow Mouse Obesity Syndrome and Mechanisms of Agouti-Induced Obesity

The yellow mouse obesity syndrome is due to dominant mutations at the Agouti locus, which is characterized by obesity, hyperinsulinemia, insulin resistance, hyperglycemia, hyperleptinemia, increased linear growth, and yellow coat color. This syndrome is caused by ectopic expression of Agouti in multiple tissues. Mechanisms of Agouti action in obesity seem to involve, at least in part, competitive melanocortin antagonism. Both central and peripheral effects have been implicated in Agouti-induced obesity. An Agouti-Related Protein (AGRP) has been described recently. It has been shown to be expressed in mice hypothalamus and to act similarly to agouti as a potent antagonist to central melanocortin receptor MC4-R, suggesting that AGRP is an endogenous MC4-R ligand. Mice lacking MC4-R become hyperphagic and develop obesity, implying that agouti may lead to obesity by interfering with MC4-R signaling in the brain and consequently regulating food intake. Furthermore, food intake is inhibited by intracerebro-ventricular injection of a potent melanocortin agonist and was reversed by administration of an MC4-R antagonist. The direct cellular actions of Agouti include stimulation of fatty acid and triglyceride synthesis via a Ca²⁺-dependent mechanism. Agouti and insulin act in an additive manner to increase lipogenesis. This additive effect of agouti and insulin is demonstrated by the necessity of insulin in eliciting weight gain in transgenic mice expressing agouti specifically in adipose tissue. This suggests that agouti expression in adipose tissue combined with hyperinsulinemia may lead to increased adiposity. The roles of melanocortin receptors or agouti-specific receptor(s) in agouti regulation of adipocyte metabolism and other peripheral effects remain to be determined. In conclusion, both central and peripheral actions of agouti contribute to the yellow mouse obesity syndrome and this action is mediated at least in part by antagonism with melanocortin receptors and/or regulation of intracellular calcium.     

Prevention of Obesity in Middle-Aged Monkeys: Food Intake During Body Weight Clamp

Prevention of obesity and increase in longevity in obesity-prone rodents can be achieved by long-term moderate dietary restriction. In order to examine the likelihood that caloric restriction could have similar salutary effects in humans, rhesus monkeys, after reaching mature adult stature, were placed on a protocol to clamp or stabilize body weight by weekly caloric adjustment Further weight gain was prevented by this caloric titration procedure, and thus middle-age onset obesity, which is very common in this species, was prevented. The present study analyzed daily food intake for six weight-clamped monkeys and six ad libitum fed age-matched animals over a 3- year period, ages 18.5 to 21.5 years. After approximately 9 years of caloric restriction the daily calorie load to maintain stable adult body weight proved to be 40% less than the amount ingested by ad libitum fed animals. Calories per kg body weight did not differ significantly between the groups although the ad libitum fed animals were significantly fatter than the weight-clamped group. Prevention of obesity using this weight clamp protocol has also maintained lower insulin levels and higher glucose tolerance in the restricted animals.     

Carbohydrate—Fat Interactions and Obesity Examined by a Two‐Compartment Computer Model

Objective: A systems dynamics computer model was developed to examine how the interactions between carbohydrate and fat metabolism influence body weight regulation. It reflects the operation of a two reservoir‐system: one representing the body's limited glycogen, and the other, its large fat reserves. The outflows from the reservoirs correspond to the oxidation of glucose and fat, whose relative contributions are affected by the size of the prevailing glycogen and fat reserves. Together, they meet the body's energy expenditure. Replenishments occur three times per day, in portions restoring total glycogen content to specific levels. A parameter mimicking the action of insulin is necessary to create realistic responses. Research Methods and Procedures: The model was run for 125‐day periods to establish the degree of adiposity for which rates of fat oxidation become commensurate with fat intake and the influence thereon of various dietary, environmental, lifestyle, and inherited variables. Results: Equivalent degrees of adiposity can be sustained under a variety of conditions. For instance, the impact on steady‐state body fat contents of a 10% increase or decrease in the energy provided by dietary fat is offset by a 26‐gram decrease or increase in mean glycogen levels. Discussion: Environmental factors such as food diversity, palatability, and availability can be expected to raise the range within which glycogen levels are habitually maintained. This restrains fat oxidation, until expansion of the fat mass is sufficient to promote fat oxidation to a rate commensurate with dietary fat intake. This metabolic leverage can explain why increased food offerings tend to raise the prevalence of obesity.     

Plasticity of Brain α-Adrenoceptors During the Development of Diet-Induced Obesity in the Rat

Male Sprague-Dawley rats, which are prone to develop diet-induced obesity (DIO) on a high energy (HE) diet can be separated from rats which are diet-resistant (DR) by several prospective tests. Using such tests, chow-fed DR-prone rats have higher binding of ³H paraminoclonidine (PAC) to brain α₂-adrenoceptors than do DIO-prone rats. These differences disappear after 3 months on a HE diet. To study the predictive value of these tests and possible associated changes in presynaptic membrane composition, brain α₁-(1nM ³H prazosin) and α₂-adrenoceptor (1nM ³H PAC) binding and synaptosomal fatty acid composition were assessed in 3-month-old male rats separated by weight gain into DR and DIO groups after 1 month on a HE diet. DIO had comparable total caloric intake but gained 30% and 43% more weight and were hyperinsulinemic compared to DR and chow-fed rats, respectively. After 1 month on a HE diet, DR rats still had 15%-53% higher ³H PAC binding than DIO and/or chow-fed rats in 14 of 16 brain areas assessed. A phenotype effect was present primarily in the amygdala where DR rats had higher ³H PAC binding than DIO rats. A diet effect was seen in some hypothalamic nuclei where both DR and DIO rats had higher ³H PAC binding than chow-fed rats. Conversely, DIO rats had 14%–21% higher ³H prazosin binding than DR rats in 3 brain areas. Changes in brain synaptosomal membranes' fatty acids reflected both phenotype and diet effects. Thus, while diet composition affects presynaptic membrane composition and α₂-adrenoceptor binding in both DR and DIO rats, the predominance of plasticity of these parameters is limited to the brains of DR rats. This suggests that such plasticity may be an important determinant of the ability to resist the development of diet-induced obesity on a HE diet.     

Transcriptome and DNA Methylome Analysis in a Mouse Model of Diet-Induced Obesity Predicts Increased Risk of Colorectal Cancer

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The Association between Plasma Adiponectin and Insulin Sensitivity in Humans Depends on Obesity

Objective: In humans, low plasma adiponectin concentrations precede a decrease in insulin sensitivity and predict type 2 diabetes independently of obesity. However, it is possible that the contribution of adiponectin to insulin sensitivity is not equally strong over the whole range of obesity. Research Methods and Procedures: We investigated the cross‐sectional association between plasma adiponectin levels and insulin sensitivity in different ranges of body fat content [expressed as percentage of body fat (PFAT)] in a large cohort of normal glucose‐tolerant subjects (n = 900). All individuals underwent an oral glucose tolerance test (OGTT), and 299 subjects additionally a euglycemic hyperinsulinemic clamp. In longitudinal analyses, the association of adiponectin at baseline with change in insulin sensitivity was investigated in a subgroup of 108 subjects. Results: In cross‐sectional analyses, the association between plasma adiponectin and insulin sensitivity, adjusted for age, gender, and PFAT, depended on whether subjects were lean or obese [p for interaction adiponectin × PFAT = <0.001 (OGTT) and 0.002 (clamp)]. Stratified by quartiles of PFAT, adiponectin did not correlate significantly with insulin sensitivity in subjects in the lowest PFAT quartile (R² = 0.10, p = 0.13, OGTT; and R² = 0.10, p = 0.57, clamp), whereas the association in the upper PFAT quartile was rather strong (R² = 0.36, p < 0.0001, OGTT; and R² = 0.48, p = 0.003, clamp). In longitudinal analyses, plasma adiponectin at baseline preceded change in insulin sensitivity in obese (n = 54, p = 0.03) but not in lean (n = 54, p = 0.68) individuals. Discussion: These data suggest that adiponectin is especially critical in sustaining insulin sensitivity in obese subjects. Thus, interventions to reduce insulin resistance by increasing adiponectin concentrations may be effective particularly in obese, insulin‐resistant individuals.     

An overview about DNA methylation in childhood obesity: Characteristics of the studies and main findings

Childhood obesity is a global burden affecting millions of children worldwide. It is well-known that the adiposity profile in children is critical for future occurrence of diseases. As a multifactorial disease, obesity is associated with genetic and environmental factors. Epigenetic mechanisms link the plethora of environmental clues to a given phenotype. DNA methylation is the most studied epigenetic mark and its importance in several diseases was acknowledged. In childhood obesity, specifically, the studies show a consistent association between adiposity and methylation at the gene and genome-wide scales. The relationship between DNA methylation and childhood obesity has been proved strong for some genes and pathways. However, the studies are heterogeneous in their design, methodologies, and results. The aim of this review is to discuss this heterogeneity and point out some aspects that should be considered in future studies to clarify the role of DNA methylation in childhood obesity.