Caloric restriction in humans reveals immunometabolic regulators of health span.

The extension of life span driven by 40% caloric restriction (CR) in rodents causes trade-offs in growth, reproduction, and immune defense that make it difficult to identify therapeutically relevant CR-mimetic targets. We report that about 14% CR for 2 years in healthy humans improved thymopoiesis and was correlated with mobilization of intrathymic ectopic lipid. CR-induced transcriptional reprogramming in adipose tissue implicated pathways regulating mitochondrial bioenergetics, anti-inflammatory responses, and longevity. Expression of the gene Pla2g7 encoding platelet activating factor acetyl hydrolase (PLA2G7) is inhibited in humans undergoing CR. Deletion of Pla2g7 in mice showed decreased thymic lipoatrophy, protection against age-related inflammation, lowered NLRP3 inflammasome activation, and improved metabolic health. Therefore, the reduction of PLA2G7 may mediate the immunometabolic effects of CR and could potentially be harnessed to lower inflammation and extend the health span.

Validity of four commercially available metabolic carts for assessing resting metabolic rate and respiratory exchange ratio in non-ventilated humans.

BACKGROUND & AIMS: The validity of most commercially available metabolic cart is mostly unknown. Thus, we aimed to determine the accuracy, precision, within-subject reproducibility, and concordance of RMR and RER measured by four commercially available metabolic carts [Cosmed Q-NRG, Vyaire Vyntus CPX, Maastricht Instruments Omnical, and Medgraphics Ultima CardiO2]. Further, we studied whether a previously proposed simulation-based post-calorimetric calibration of cart readouts [individual calibration control evaluation (ICcE)] modify the RMR and RER reproducibility and concordance. METHODS: Three experiments simulating different RMR and RER by controlled pure gas (N2 and CO2) infusions were conducted on 5 non-consecutive days. Moreover, 30-min methanol burns were performed on 3 non-consecutive days. Lastly, the RMR and RER of 29 young non-ventilated adults (11 women; 25 ± 4 years-old; BMI: 24.1 ± 3.2 kg/m2) were assessed twice using each instrument, 24 hours apart, under standardized conditions. RESULTS: The Omnical presented the lowest measurement error for RER (Omnical = 1.7 ± 0.9%; Vyntus = 4.5 ± 2.0%; Q-NRG = 6.6 ± 1.9%; Ultima = 6.8 ± 6.5%) and EE (Omnical = 1.5 ± 0.5%; Q-NRG = 2.5 ± 1.3%; Ultima = 10.7 ± 11.0%; Vyntus = 13.8 ± 5.0%) in all in vitro experiments (controlled pure gas infusions and methanol burns). In humans, the 4 metabolic carts provided discordant RMR and RER estimations (all P < 0.001). No differences were detected in RMR within-subject reproducibility (P = 0.058; Q-NRG inter-day coefficient of variance = 3.6 ± 2.5%; Omnical = 4.8 ± 3.5%; Vyntus = 5.0 ± 5.6%; Ultima = 5.7 ± 4.6%), although the Ultima CardiO2 provided larger RER inter-day differences (4.6 ± 3.5%) than the others carts (P = 0.001; Omnical = 1.9 ± 1.7%; Vyntus = 2.1 ± 1.3%; Q-NRG = 2.4 ± 2.1%). The ICcE procedure did not modify the RMR or RER concordance and did not reduce the inter-day differences in any of the carts. CONCLUSIONS: The 4 metabolic carts provided discordant measurements of RMR and RER. Overall, the Omnical provides more accurate and precise estimations of RMR and RER than the Q-NRG, Vyntus and Ultima CardiO2, and might be considered the best for assessing RMR and RER in non-ventilated humans. Finally, our results do not support the use of an ICcE procedure.

One-year caloric restriction and 12-week exercise training intervention in obese adults with type 2 diabetes: emphasis on metabolic control and resting metabolic rate.

PURPOSE: The effect of combined lifestyle interventions (LSI) including dietary and physical activity on metabolic health, energy metabolism and VO2max in diabetic patients has provided mixed results. We evaluated the impact of 1-year caloric restriction (CR), and 12-week supervised structured exercise training (SSET) on metabolic health, RMR and VO2max in obese adults with type 2 diabetes. METHODS: After 1-month education for LSI, 33 participants had anthropometric, biochemical and metabolic assessments. They then started CR based on RMR, and 3-month SSET during the months 1-3 (Early-SSET) or 4-6 (Late-SSET). Reassessments were planned after 3, 6 and 12 months. Using a per-protocol analysis, we evaluated parameter changes from baseline and their associations for the 23 participants (11 Early-SSET, 12 Late-SSET) who completed the study. RMR was adjusted (adjRMR) for age, sex, fat-free mass (FFM) and fat mass (FM). RESULTS: Compared with baseline, after 6 months we found significant increases in VO2max (+ 14%) and HDL-cholesterol (+ 13%), and reduction in body mass index (- 3%), FM (- 8%) and glycated hemoglobin (HbA1c, - 7%). Training-related caloric expenditure negatively correlated with changes in body weight (p < 0.001), FM (p < 0.001) and HbA1c (p = 0.006). These results were confirmed at the 12-month follow-up. Pooling together all follow-up data, adjRMR changes correlated with changes in glycemia (r = 0.29, p = 0.02), total-cholesterol (r = 0.29, p = 0.02) and VO2max (r = - 0.26,p = 0.02). No significant differences emerged between the Early- and Late-SSET groups. CONCLUSIONS: Combined intervention with SSET and CR improved metabolic control. Changes in metabolic health and fitness correlated with changes of adjRMR, which was reduced improving fitness, glycemia and cholesterolemia. CLINICAL TRIAL REGISTRY: Trial registration number: NCT03785379. URL of registration: http://clinicaltrials.gov .

Pathways and mechanisms linking dietary components to cardiometabolic disease: thinking beyond calories.

Calories from any food have the potential to increase risk for obesity and cardiometabolic disease because all calories can directly contribute to positive energy balance and fat gain. However, various dietary components or patterns may promote obesity and cardiometabolic disease by additional mechanisms that are not mediated solely by caloric content. Researchers explored this topic at the 2017 CrossFit Foundation Academic Conference 'Diet and Cardiometabolic Health - Beyond Calories', and this paper summarizes the presentations and follow-up discussions. Regarding the health effects of dietary fat, sugar and non-nutritive sweeteners, it is concluded that food-specific saturated fatty acids and sugar-sweetened beverages promote cardiometabolic diseases by mechanisms that are additional to their contribution of calories to positive energy balance and that aspartame does not promote weight gain. The challenges involved in conducting and interpreting clinical nutritional research, which preclude more extensive conclusions, are detailed. Emerging research is presented exploring the possibility that responses to certain dietary components/patterns are influenced by the metabolic status, developmental period or genotype of the individual; by the responsiveness of brain regions associated with reward to food cues; or by the microbiome. More research regarding these potential 'beyond calories' mechanisms may lead to new strategies for attenuating the obesity crisis.

Eight weeks of overfeeding alters substrate partitioning without affecting metabolic flexibility in men.

BACKGROUND/OBJECTIVE: Impairments in metabolic flexibility (MF) and substrate handling are associated with metabolic syndrome. However, it is unknown whether metabolic inflexibility causes insulin resistance. We therefore measured MF and substrate handling before and after 8 weeks of overfeeding in initially healthy adults as a model of the early stages of insulin resistance. SUBJECTS/METHODS: Twenty-nine healthy men (27±5 years old; body mass index 25.5±2.3 kg m-2) were overfed by 40% above baseline energy requirements for 8 weeks and gained 7.6±2.1 kg of weight. Before and after overfeeding, energy expenditure, substrate oxidation and MF were measured in two ways: (a) during 1 day of eucaloric feeding in a whole-room indirect calorimeter and (b) during a two-step hyperinsulinemic-euglycemic clamp. RESULTS: Eight weeks of overfeeding decreased insulin sensitivity at low and high doses of insulin (P=0.001 and P=0.06, respectively). This was accompanied by decreases in the respiratory quotient (RQ) while sleeping (from 0.877±0.020 to 0.864±0.026; P=0.05) and at low insulin levels during the clamp (from 0.927±0.047 to 0.907±0.032; P=0.01). Overfeeding did not affect MF as measured during a clamp (P⩾0.17), but it tended to increase 24-h MF (awake RQ-sleep RQ) as measured by chamber by 0.010±0.028 (P=0.08). In terms of substrate oxidation, overfeeding increased protein oxidation by 13±23 g day-1 (P=0.003) and tended to increase fat oxidation by 6±16 g day-1 (P=0.07) but did not affect carbohydrate oxidation (P=0.64). Individuals with greater metabolic adaptation to overfeeding had higher carbohydrate oxidation rates (r=0.66, P=8 × 10-5) but not fat oxidation rates (P=0.09). CONCLUSIONS: The early stages of insulin resistance are accompanied by modest declines in the RQs during sleep and during a clamp, with no changes in fasting RQ or signs of metabolic inflexibility. Our data therefore suggest that metabolic inflexibility does not cause insulin resistance.

Indirect calorimetry: an indispensable tool to understand and predict obesity.

Obesity is a physiological condition of chronic positive energy balance. While the regulation of energy metabolism varies widely among individuals, identifying those who are metabolically prone to weight gain and intervening accordingly is a key challenge for reversing the course of the obesity epidemic. Indirect calorimetry is the most commonly used method to measure energy expenditure in the research setting. By measuring oxygen consumption and carbon dioxide production, indirect calorimetry provides minute-by-minute energy expenditure data that makes it the most valuable tool to distinguish the various components of energy expenditure, that is, sleeping and resting metabolic rate, thermic effect of food and the energy cost of activity. Importantly, such measures also provide information on energy substrate utilization. Here we summarized some of the research that revealed resting metabolic rate, spontaneous physical activity and respiratory quotient as key metabolic predictors of weight gain and obesity. Recent studies using indirect calorimetry in response to mid-term fasting or overfeeding have identified 'thrifty' and 'spendthrift' phenotypes in people who differ in propensity to weight gain. We propose the use of indirect calorimetry data as a basis for personalized interventions that may be efficacious in slowing down the rise of global obesity.

Assessment of EchoMRI-AH versus dual-energy X-ray absorptiometry by iDXA to measure human body composition.

Comparison of percent fat mass across different body composition analysis devices is important given variation in technology accuracy and precision, as well as the growing need for cross-validation of devices often applied across longitudinal studies. We compared EchoMRI-AH and Lunar iDXA quantification of percent body fat (PBF) in 84 adults (43M, 41F), with the mean age 39.7±15.9 years and body mass index (BMI) 26.2±5.3 kg/m2. PBF correlated strongly between devices (r>0.95, P<0.0001). A prediction equation was derived in half of the subjects, and the other half were used to cross-validate the proposed equation (EchoMRI-AH PBF=[(0.94 × iDXA PBF)+(0.14 × Age)+(3.3 × Female)-8.83). The mean PBF difference (predicted-measured) in the validation group was not different from 0 (diff=0.27%, 95% confidence interval: -0.42-0.96, P=0.430). Bland-Altman plots showed a bias with higher measured PBF on EchoMRI-AH versus iDXA in all 84 subjects (ß=0.13, P<0.0001). The proposed prediction equation was valid in our cross-validation sample, and it has the potential to be applied across multicenter studies.

Eight weeks of dietary overfeeding increases renal filtration rates in humans: implications for the pathogenesis of diabetic hyperfiltration.

OBJECTIVE: Diabetic nephropathy is characterized at its onset by glomerular hyperfiltration. Prospective studies in humans measuring filtration rates with weight gain are lacking. We investigated renal filtration following weight gain induced by overfeeding. DESIGN: Eight weeks of overfeeding (40% above energy requirements, 44% fat, 15% protein and 41% carbohydrate) as well as a 6-month follow-up after the overfeeding intervention. SUBJECTS: Thirty-five participants (age: 26.7 ±5.3 years; body mass index: 25.5 ± 2.2 kg m(-2) ; 29 m/6f). MEASUREMENTS: Creatinine clearance rate (Ccr) from 24-h urine collection, estimated glomerular filtration rate (eGFR) from the modification of diet in renal disease (MDRD), insulin sensitivity/glucose disposal rate (GDR) by a euglycemic-hyperinsulinemic clamp, components from basic metabolic panels and serum lipid panels. RESULTS: Both eGFR and Ccr increased with overfeeding (P = 0.04) and serum lipids (all P < 0.05), along with a decrease in insulin sensitivity (P = 0.003). Fasting glucose concentration was not affected (P = 0.98), but the per cent change in Ccr correlated positively with the change in GDR with overfeeding (r = 0.39, P = 0.02). Six months following overfeeding, serum glucose was maintained, and no evidence of urinary glucose was observed at any time-point. CONCLUSIONS: These data suggest that renal hyperfiltration may act as a mechanism to preserve insulin sensitivity through maintenance of systemic glucose homoeostasis with caloric excess.

Metabolically healthy and unhealthy obese--the 2013 Stock Conference report.

Obesity is closely associated with cardiovascular diseases and type 2 diabetes, but some obese individuals, despite having excessive body fat, exhibit metabolic health that is comparable with that of lean individuals. The 'healthy obese' phenotype was described in the 1980s, but major advancements in its characterization were only made in the past five years. During this time, several new mechanisms that may be involved in health preservation in obesity were proposed through the use of transgenic animal models, use of sophisticated imaging techniques and in vivo measurements of insulin sensitivity. However, the main obstacle in advancing our understanding of the metabolically healthy obese phenotype and its related long-term health risks is the lack of a standardized definition. Here, we summarize the proceedings of the 13th Stock Conference of the International Association of the Study of Obesity. We describe the current research and highlight the unanswered questions and gaps in the field. Better understanding of metabolic health in obesity will assist in therapeutic decision-making and help identify therapeutic targets to improve metabolic health in obesity.

Inverse correlation of serum inflammatory markers with metabolic parameters in healthy, Black and White prepubertal youth.

OBJECTIVE: To examine for the first time the associations between pro-inflammatory cytokines and obesity-related metabolic biomarkers in, exclusively prepubertal, otherwise healthy obese and non-obese Black and White children, 7-9 years of age. DESIGN AND METHODS: Body mass index (BMI), homeostasis model assessment-estimated insulin resistance, visceral adipose tissue and subcutaneous adipose tissue (SAT (magnetic resonance imaging)); total body fat (dual-energy X-ray absorptiometry), ectopic, intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) fat (proton magnetic resonance spectroscopy) and serum levels of interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1 were measured in 40 obese and non-obese children. Relationships between inflammatory cytokines and obesity were assessed by analysis of variance and Spearman's rank correlation. RESULTS: Significant inverse correlations were found between BMI z-score, SAT, total BF, and IHL and levels of TNF-α (Spearman's ρ=-0.36, -0.39, -0.43 and -0.39, respectively; P<0.05). Levels of IL-8 were significantly and inversely correlated with IMCL (-0.39; P=0.03) and remained significant after adjusting for race. IMCL was inversely associated with TNF-α only after adjusting for race (-0.37; P=0.04). CONCLUSIONS: Relationships between pro-inflammatory and metabolic markers commonly observed in adults are reversed in healthy, Black and White children before puberty. Prospective studies are warranted to determine how these inverse relationships modify chronic disease risk later in life.

Activity related energy expenditure, appetite and energy intake: potential implications for weight management.

The aim was to investigate relationships between activity related energy expenditure (AREE), appetite ratings and energy intake (EI) in a sample of 40 male (26.4years; BMI 23.5kg/m(2)) and 42 female (26.9years; BMI 22.4kg/m(2)) participants. AREE was expressed as the residual value of the regression between total daily EE (by doubly labeled water) and resting EE (by indirect calorimetry). EI was measured using an ad libitum buffet meal and visual analogue scales measured subjective appetite ratings before and after the meal. AREE was divided into low, middle and high sex-specific tertiles. General linear models were used to investigate differences in appetite ratings and EI across AREE tertiles. Before the meal, males in the high AREE tertile had significantly lower desire to eat and lower prospective food consumption and higher feelings of fullness compared to those in the low tertile. Males in the middle tertile had significantly higher satiety quotients after the meal and lower EI compared to the other tertiles. No significant differences across tertiles were found in females. Sex differences in relationships between AREE, appetite ratings and EI may lead to differing patterns of EI and subsequent weight maintenance.

Postprandial whole-body glycolysis is similar in insulin-resistant and insulin-sensitive non-diabetic humans.

AIMS/HYPOTHESIS: Insulin resistance is characterised by impaired glucose utilisation when measured by a euglycaemic-hyperinsulinaemic clamp. We hypothesised that, in response to postprandial conditions, non-diabetic individuals would have similar intracellular glycolytic and oxidative glucose metabolism independent of the degree of insulin resistance. METHODS: Fourteen (seven male) sedentary, insulin-sensitive participants (mean ± SD: BMI 25 ± 4 kg/m²; age 39 ± 10 years; glucose disposal rate 9.4 ± 2.1 mg [kg estimated metabolic body size]⁻¹ min⁻¹) and 14 (six male) sedentary, non-diabetic, insulin-resistant volunteers (29 ± 4 kg/m²; 34 ± 13 years; 5.3 ± 1.2 mg [kg estimated metabolic body size]⁻¹ min⁻¹) received after a 10 h fast 60 g glucose plus 15 g [6,6-²H2]glucose. Serum glucose and insulin concentrations, plasma ²H enrichment and whole-body gas exchange were determined before glucose ingestion and hourly thereafter for 4 h. Plasma ²H2O production is an index of glycolytic disposal. On day 2, participants received a weight-maintenance diet. On day 3, a euglycaemic-hyperinsulinaemic clamp was performed. RESULTS: Insulin-resistant individuals had about a twofold higher postprandial insulin response than insulin-sensitive individuals (p = 0.003). Resting metabolic rate was similar in the two groups before (p = 0.29) and after (p = 0.33-0.99 over time) glucose ingestion, whereas a trend for blunted glucose-induced thermogenesis was observed in insulin-resistant vs insulin-sensitive individuals (p = 0.06). However, over the 4 h after the 75 g glucose ingestion, glycolytic glucose disposal was the same in insulin-sensitive and insulin-resistant individuals (36.5 ± 3.7 and 36.2 ± 6.4 mmol, respectively; p = 0.99). Similarly, whole-body carbohydrate oxidation did not differ between the groups either before or after glucose ingestion (p = 0.41). CONCLUSIONS/INTERPRETATION: Postprandial hyperinsulinaemia and modest hyperglycaemia overcome insulin resistance by enhancing tissue glucose uptake and intracellular glucose utilisation.

Could the mechanisms of bariatric surgery hold the key for novel therapies? report from a Pennington Scientific Symposium.

Bariatric surgery is the most effective method for promoting dramatic and durable weight loss in morbidly obese subjects. Furthermore, type 2 diabetes is resolved in over 80% of patients. The mechanisms behind the amelioration in metabolic abnormalities are largely unknown but may be due to changes in energy metabolism, gut peptides and food preference. The goal of this meeting was to review the latest research to better understand the mechanisms behind the 'magic' of bariatric surgery. Replication of these effects in a non-surgical manner remains one of the ultimate challenges for the treatment of obesity and diabetes. Promising data on energy metabolism, gastrointestinal physiology, hedonic response and food intake were reviewed and discussed.

Assessment of EchoMRI-AH versus dual-energy X-ray absorptiometry to measure human body composition.

BACKGROUND: The sensitivity to detect small changes in body composition (fat mass and fat-free mass) largely depends on the precision of the instrument. We compared EchoMRI-AH and dual-energy X-ray absorptiometry (DXA) (Hologic QDR-4500A) for estimating fat mass in 301 volunteers. METHODS: Body composition was evaluated in 136 males and 165 females with a large range of body mass index (BMI) (19-49 kg m(-2)) and age (19-91 years old) using DXA and EchoMRI-AH. In a subsample of 13 lean (BMI=19-25 kg m(-2)) and 21 overweight/obese (BMI>25 kg m(-2)) individuals, within-subject precision was evaluated from repeated measurements taken within 1 h (n=3) and 1 week apart (mean of three measurements taken on each day). RESULTS: Using Bland-Altman analysis, we compared the mean of the fat mass measurements versus the difference in fat mass measured by both instruments. We found that EchoMRI-AH quantified larger amount of fat versus DXA in non-obese (BMI<30 kg m(-2) (1.1 kg, 95% confidence interval (CI(95)):-3.7 to 6.0)) and obese (BMI ≥ 30 kg m(-2) (4.2 kg, CI(95):-1.4 to 9.8)) participants. Within-subject precision (coefficient of variation, %) in fat mass measured within 1 h was remarkably better when measured by EchoMRI-AH than DXA (<0.5 versus <1.5%, respectively; P<0.001). However, 1-week apart within-subject variability showed similar values for both instruments (<2.2%; P=0.15). CONCLUSIONS: EchoMRI-AH yielded greater fat mass values when compared with DXA (Hologic QDR-4500A), particularly in fatter subjects. EchoMRI-AH and DXA showed similar 1-week apart precision when fat mass was measured both in lean and overweight/obese individuals.

Intrahepatic and intramyocellular lipids are determinants of insulin resistance in prepubertal children.

AIMS/HYPOTHESIS: We hypothesised that ectopic fat deposition is present in liver and skeletal muscle before puberty and that both are potentially important factors in the early pathogenesis of insulin resistance. METHODS: Proton magnetic resonance spectroscopy was used to evaluate intramyocellular and intrahepatic lipids in 50 male and 42 female multi-ethnic, prepubertal (Tanner < 2) children (8.1 ± 0.8 years; 35.4 ± 10.7 kg; 27.9 ± 8.3% body fat; means ± SD). Intramyocellular lipid was measured in soleus muscle and intrahepatic lipid in the middle right lobe. Abdominal fat was measured by magnetic resonance imaging, body fat by dual energy X-ray absorptiometry, and insulin resistance using homeostatic model assessment. RESULTS: Intrahepatic lipid ranged from 0.11% to 4.6% relative to the liver water signal (mean 0.79 ± 0.79%) whereas intramyocellular lipid ranged from 0.13% to 1.86% relative to the muscle water signal (mean 0.51 ± 0.28%). Intramyocellular and intrahepatic lipids were significantly correlated with total adiposity (r = 0.49 and 0.59), abdominal adiposity (r = 0.44 and 0.54), and each other (r = 0.39, p < 0.05, Spearman). Both intramyocellular and intrahepatic lipid were positively correlated with fasting insulin (r = 0.37 and 0.38 respectively) and insulin resistance (r = 0.37 and 0.37; p < 0.01). After adjustment for race and sex, the relations between ectopic fat and insulin resistance remained, whereas both disappeared when further adjusted for body fat or BMI z scores. CONCLUSIONS/INTERPRETATIONS: These results suggest that typical relations between body composition, ectopic fat and insulin resistance are present in children before puberty. Thus, interventions aimed at reducing adiposity have the potential to decrease ectopic fat accumulation, delay the onset of insulin resistance and decrease the risk for development of type 2 diabetes in children.

Abdominal adiposity depots are correlates of adverse cardiometabolic risk factors in Caucasian and African-American adults.

OBJECTIVE: Accumulation of adipose tissue is associated with cardiometabolic risks. Although visceral adipose tissue (VAT) has been strongly implicated in this relationship, there is still some debate regarding the contribution of abdominal subcutaneous adipose tissue (SAT). The purpose of this study was to determine the contribution of abdominal SAT to cardiometabolic risk factors, independent of total and visceral adiposity. These relationships were assessed in Caucasian and African Americans. DESIGN: It is a cross-sectional analysis of the Pennington Center Longitudinal Study. SUBJECTS: Data were extracted from 1246 participants. Total body fat mass (FM) was measured by dual-energy X-ray absorptiometry, whereas abdominal VAT and SAT areas (cm(2)) were measured with computed tomography. The cardiometabolic risk factors included resting blood pressure (BP), fasting blood glucose and triglyceride concentrations and high-density lipoprotein cholesterol (HDL-C). RESULTS: Positive relationships across tertiles of VAT were seen for the participants with high glucose, high BP and low HDL-C (P<0.043). There was also a significant increase in the percentage of participants with two or more cardiometabolic risk factors across most tertiles of abdominal SAT (P<0.042). Logistic regression analysis showed that in univariate models, all adiposity measures were significantly associated with increased odds of having all risk factors in men and women. In multivariate models, VAT was significantly associated with most risk factors across gender. Abdominal SAT and FM (odds ratios (ORs) 1.3-2.1; all P<0.05) were associated with fewer risk factors after accounting for VAT. VAT (OR=5.9 and 5.3) and SAT (OR=2.0 and 1.8) were both associated with higher odds of the presence of two or more cardiometabolic risk factors in both males and females (P<0.001). CONCLUSION: The data suggest that abdominal SAT is not protective against unfavorable cardiometabolic risk profiles. These conclusions were consistent across ethnic groups.

Lorcaserin for the treatment of obesity.

Obesity is a worldwide epidemic and there is an urgent need for the development of effective pharmacological therapies that target the metabolic and behavioral factors of body weight regulation. Serotonin (5-HT) has been implicated as a critical factor in the short-term (meal-by-meal) regulation of food intake and pharmaceutical companies have invested millions of dollars to discover and develop drug targets for the serotonergic pathway. Lorcaserin is a novel selective agonist of the 5-HT(2C) receptor for weight loss therapy. Preclinical and clinical studies indicate lorcaserin is well tolerated and not associated with cardiac valvulopathy or pulmonary hypertension suggesting that lorcaserin is a selective 5-HT(2C) receptor agonist and has little or no activation of the 5-HT(2B) and 5-HT(2A) receptors, respectively. Lorcaserin acts to alter energy balance through a reduction in energy intake and without an increase in energy expenditure and achieved the U.S. Food and Drug Administration guidelines for weight loss efficacy. It remains to be determined whether or not lorcaserin will be approved for the long-term management of obesity.

mRNA concentrations of MIF in subcutaneous abdominal adipose cells are associated with adipocyte size and insulin action.

OBJECTIVE: To determine whether the mRNA concentrations of inflammation response genes in isolated adipocytes and in cultured preadipocytes are related to adipocyte size and in vivo insulin action in obese individuals. DESIGN: Cross-sectional inpatient study. SUBJECTS: Obese Pima Indians with normal glucose tolerance. MEASUREMENTS: Adipocyte diameter (by microscope technique; n=29), expression of candidate genes (by quantitative real-time PCR) in freshly isolated adipocytes (monocyte chemoattractant protein (MCP) 1 and MCP2, macrophage inflammatory protein (MIP) 1alpha, MIP1beta and MIP2, macrophage migration inhibitory factor (MIF), tumor necrosis factor alpha, interleukin (IL) 6 and IL8; n=22) and cultured preadipocytes (MCP1, MIP1alpha, MIF, IL6 and matrix metalloproteinase 2; n=33) from subcutaneous abdominal adipose tissue (by aspiration biopsy, n=34), body fat by dual-energy X-ray absorptiometry, glucose tolerance by 75 g oral glucose tolerance test and insulin action by euglycemic-hyperinsulinemic clamp (insulin infusion rate 40 mU m(-2) min(-1)) (all n=34). RESULTS: MIF was the only gene whose expression in both freshly isolated adipocytes and cultured preadipocytes was positively associated with adipocytes diameter and negatively associated with peripheral and hepatic insulin action (all P<0.05). In multivariate analysis, the association between adipocyte MIF mRNA concentrations and adipocytes diameter was independent of the percentage of body fat (P=0.03), whereas adipocyte MIF mRNA concentrations, but not adipocyte diameter, independently predicted peripheral insulin action. The mRNA expression concentrations of the MIF gene in adipocytes were not associated with plasma concentrations of MIF, but were negatively associated with plasma adiponectin concentrations (P=0.004). In multivariate analysis, adipocyte MIF RNA concentrations (P=0.03) but not plasma adiponectin concentrations (P=0.4) remained a significant predictor of insulin action. CONCLUSIONS: Increased expression of MIF gene in adipose cells may be an important link between obesity characterized by enlarged adipocytes and insulin resistance in normal glucose tolerant people.

Effect of calorie restriction on subjective ratings of appetite.

BACKGROUND: Energy or calorie restriction (CR) has consistently been shown to produce weight loss and have beneficial health effects in numerous species, including primates and humans. Most individuals, however, are unable to sustain weight losses induced through reductions in energy intake, potentially due to increased hunger levels. The effects that prolonged CR has on subjective aspects of appetite have not been well studied. Thus, the present study tested the effect of 6 months of caloric restriction on appetite in healthy, overweight men and women. METHODS: Forty-eight overweight men and women with a body mass index (BMI; kg m(-2)) between 25-29.9 took part in a 6-month study and were randomised into one of four groups: healthy diet (control); 25% CR; 12.5% CR plus exercise (12.5% increased energy expenditure; CR + EX); low-calorie diet [LCD; 3724 kJ day(-1) (890 kcal day(-1)) until 15% of initial body weight was lost, then maintenance]. Appetite markers (i.e. hunger, fullness, desire to eat, etc.) were assessed weekly during a fasting state. RESULTS: Body weight was significantly reduced in all three energy-restricted groups (CR = -10.4 +/- 0.9%; CR + EX = -10.0 +/- 0.8%; and LCD = -13.9 +/-0.7%), indicating that participants were adherent to their energy restriction regimen, whereas the healthy diet control group remained weight stable (control = -1.0 +/- 1.1%). Despite these significant weight losses, appetite ratings of participants in the three energy-restricted groups at month 6 were similar to the weight stable control group. CONCLUSIONS: CR regimens with low fat diets producing significant weight losses have similar effects on appetite markers over a 6-month time period compared to a weight stable control group.

Have we entered the brown adipose tissue renaissance?

In the 1970s and 1980s, it was observed that rodents could offset excess calories ingested when they were fed a human-like 'cafeteria diet'. Although it was erroneously concluded that this so-called diet-induced thermogenesis was because of brown adipose tissue (BAT), it led to efforts to test whether variations in brown fat in humans may explain the susceptibility to obesity. However, from evidence on the inability of ephedrine or beta-3 adrenergic agonists to induce BAT thermogenesis, it was concluded that the thermogenic role of BAT was unimportant in adult humans largely because humans had low numbers of brown adipocytes. Solid evidence on the actual numbers of brown adipocytes in humans was not available. We are now re-evaluating the role of BAT for the treatment of obesity given the following recent observations (i) studies in nuclear medicine by using PET/CT scanning reveal the presence of BAT in adult humans; and (ii) recent data suggest that a new transcription factor called PDRM16 may control the induction of BAT. These recent discoveries should revamp our effort to target the molecular development of brown adipogenesis in the treatment of obesity.