Navin Michael

Faster eating rates are associated with higher energy intakes during an ad libitum meal, higher BMI and greater adiposity among 4-5 year-old children: results from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) cohort

Faster eating rates are associated with increased energy intake, but little is known about the relationship between childrens eating rate, food intake and adiposity. We examined whether children who eat faster consume more energy and whether this is associated with higher weight status and adiposity. We hypothesised that eating rate mediates the relationship between child weight and ad libitum energy intake. Children (n 386) from the Growing Up in Singapore Towards Healthy Outcomes cohort participated in a video-recorded ad libitum lunch at 4·5 years to measure acute energy intake. Videos were coded for three eating-behaviours (bites, chews and swallows) to derive a measure of eating rate (g/min). BMI and anthropometric indices of adiposity were measured. A subset of children underwent MRI scanning (n 153) to measure abdominal subcutaneous and visceral adiposity. Children above/below the median eating rate were categorised as slower and faster eaters, and compared across body composition measures. There was a strong positive relationship between eating rate and energy intake (r 0·61, P<0·001) and a positive linear relationship between eating rate and childrens BMI status. Faster eaters consumed 75 % more energy content than slower eating children (Δ548 kJ (Δ131 kcal); 95 % CI 107·6, 154·4, P<0·001), and had higher whole-body (P<0·05) and subcutaneous abdominal adiposity (Δ118·3 cc; 95 % CI 24·0, 212·7, P=0·014). Mediation analysis showed that eating rate mediates the link between child weight and energy intake during a meal (b 13·59; 95 % CI 7·48, 21·83). Children who ate faster had higher energy intake, and this was associated with increased BMI z-score and adiposity.

Differentiating Brown and White Adipose Tissues by High-Resolution Diffusion NMR Spectroscopy

There are two types of fat tissues, white adipose tissue (WAT) and brown adipose tissue (BAT), which essentially perform opposite functions in whole body energy metabolism. There is a large interest in identifying novel biophysical properties of WAT and BAT by a quantitative and easy-to-run technique. In this work, we used high-resolution pulsed field gradient diffusion NMR spectroscopy to study the apparent diffusion coefficient (ADC) of fat molecules in rat BAT and WAT samples. The ADC of fat in BAT and WAT from rats fed with a chow diet was compared with that of rats fed with a high-fat diet to monitor how the diffusion properties change due to obesity-associated parameters such as lipid droplet size, fatty acid chain length, and saturation. Feeding a high-fat diet resulted in increased saturation, increased chain lengths, and reduced ADC of fat in WAT. The ADC of fat was lower in BAT relative to WAT in rats fed both chow and high-fat diets. Diffusion of fat was restricted in BAT due to the presence of small multilocular lipid droplets. Our findings indicate that in vivo diffusion might be a potential way for better delineation of BAT and WAT in both lean and obese states.

Effect of Exercise and Calorie Restriction on Tissue Acylcarnitines, Tissue Desaturase Indices, and Fat Accumulation in Diet-Induced Obese Rats

Both exercise and calorie restriction interventions have been recommended for inducing weight-loss in obese states. However, there is conflicting evidence on their relative benefits for metabolic health and insulin sensitivity. This study seeks to evaluate the differential effects of the two interventions on fat mobilization, fat metabolism, and insulin sensitivity in diet-induced obese animal models. After 4 months of ad libitum high fat diet feeding, 35 male Fischer F344 rats were grouped (n = 7 per cohort) into sedentary control (CON), exercise once a day (EX1), exercise twice a day (EX2), 15% calorie restriction (CR1) and 30% calorie restriction (CR2) cohorts. Interventions were carried out over a 4-week period. We found elevated hepatic and muscle long chain acylcarnitines with both exercise and calorie restriction, and a positive association between hepatic long chain acylcarnitines and insulin sensitivity in the pooled cohort. Our result suggests that long chain acylcarnitines may not indicate incomplete fat oxidation in weight loss interventions. Calorie restriction was found to be more effective than exercise in reducing body weight. Exercise, on the other hand, was more effective in reducing adipose depots and muscle triglycerides, favorably altering muscle/liver desaturase activity and improving insulin sensitivity.

Regulation of glucose metabolism in non-diabetic, metabolically-obese normal-weight Asians

Type 2 diabetes in Asia occurs largely in the absence of obesity. The metabolically obese normal-weight (MONW) phenotype refers to lean subjects with metabolic dysfunction that is typically observed in people with obesity and is associated with increased risk for diabetes. Previous studies evaluated MONW subjects who had greater body mass index (BMI) or total body fat than respective control groups, making interpretation of the results difficult. We evaluated insulin sensitivity (hyperinsulinemic-euglycemic clamp); insulin secretion (mixed meal with oral minimal modeling); intra-abdominal, muscle, and liver fat contents (magnetic resonance); and fasting and postprandial glucose and insulin concentrations in 18 MONW subjects and 18 metabolically healthy controls matched for age (43 ± 3 and 40 ± 3 yr; P = 0.52), BMI (both 22 ± 1 kg/m2; P = 0.69), total body fat (17 ± 1 and 16 ± 1 kg; P = 0.33), and sex (9 men and 9 women in each group). Compared with controls, MONW subjects had an approximately twofold greater visceral adipose tissue volume and an approximately fourfold greater intrahepatic fat content (but similar muscle fat), 20-30% lower glucose disposal rates and insulin sensitivity, and 30-40% greater insulin secretion rates (all P < 0.05). The disposition index, fasting glucose, and HbA1c concentrations were not different between groups, whereas postprandial glucose and insulin concentrations were ~15% and ~65% greater, respectively, in MONW than control subjects (both P < 0.05). We conclude that the MONW phenotype is associated with accumulation of fat in the intra-abdominal area and the liver, profound insulin resistance, but also a robust β-cell insulin secretion response that compensates for insulin resistance and helps maintain glucose homeostasis.

Moderate Weight Loss Improves Body Composition and Metabolic Function in Metabolically Unhealthy Lean Subjects: Weight Loss in MONW Subjects

Individuals who have “metabolically obese normal weight” (MONW) have an increased risk for cardiometabolic disease. Moderate weight loss has multiple benefits in people with obesity, but its effects in lean people are unknown. Thus, the effects of diet‐induced 5% weight loss on body composition and metabolic function in MONW subjects were evaluated.

Sex differences in glucose and fatty acid metabolism in non-obese Asians.

Context The prevalence of diabetes is increasing throughout Asia, even in the absence of obesity, and is lower in women than in men. The underlying mechanisms are not well understood. Objective To evaluate the sex differences in glucose and fatty acid metabolism in Asians who are nonobese. Design Cross-sectional study. Setting Clinical Nutrition Research Centre, Singapore. Participants Healthy Asian men (n = 32; body mass index, 21.8 ± 1.5 kg/m2; age, 42 ± 14 years) and women (n = 28; body mass index, 21.4 ± 2.0 kg/m2; age, 41 ± 13 years). Main Outcome Measures Insulin sensitivity (insulin-mediated glucose uptake normalized for steady-state insulin; hyperinsulinemic-euglycemic clamp), postprandial glucose, insulin and fatty acid concentrations, insulin secretion (mixed meal tolerance test with mathematical modeling), insulin clearance, body composition and fat distribution (dual-energy X-ray absorptiometry, MRI, and spectroscopy), cardiorespiratory fitness (maximal oxygen uptake; graded exercise test), and handgrip strength (dynamometry). Results Women had more total body fat but less visceral fat than men; liver and muscle lipid contents were not different. Maximal oxygen uptake and handgrip strength were lower in women than men. The postprandial glucose concentrations were ~8% lower, the insulin-mediated glucose uptake was ~16% greater, and the meal-induced suppression of fatty acid concentrations was significantly greater in women than in men (P < 0.05 for all). However, muscle insulin sensitivity was not different between the sexes. No differences were found in postprandial insulin secretion and clearance rates; however, the steady-state insulin clearance was ~17% lower in women. Conclusions Asian women who are nonobese are more insulin-sensitive than men at the level of adipose tissue but not skeletal muscle. Therefore, sex differences in glucose tolerance are likely the result of sexual dimorphism in hepatic insulin action.

Low Dose Levothyroxine Reduces Intrahepatic Lipid Content in Patients with Type 2 Diabetes Mellitus and NAFLD.

Context Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes mellitus (T2DM) and associated with significant morbidity and mortality. Thyroid hormone (TH) increases β-oxidation of fatty acids and decreases intrahepatic lipid content (IHLC) in rodents with NAFLD. Objective We investigated the possibility of low intrahepatic TH concentration in NAFLD and studied the effect of TH treatment in humans. Design/Setting This was a phase 2b single-arm study in six hospitals in Singapore. Intrahepatic thyroid hormone concentrations were measured in rats with induced NAFLD. Patients Euthyroid patients with T2DM and steatosis measured by ultrasonography. Intervention Levothyroxine was titrated to reach a thyroid-stimulating hormone level of 0.34 to 1.70 mIU/L before a 16-week maintenance phase. Main Outcome Measures The primary outcome measure was change in IHLC measured by proton magnetic resonance spectroscopy after treatment. Results Twenty male patients were included in the per-protocol analysis [mean ± SD: age, 47.8 ± 7.8 years; body mass index (BMI), 30.9 ± 4.4 kg/m2; baseline IHLC, 13% ± 4%]. After treatment, IHLC was decreased 12% (±SEM, 26%) relative to baseline (absolute change, -2%; 95% CI, -3 to 0; P = 0.046). Small decreases in BMI (P = 0.044), visceral adipose tissue volume (P = 0.047), and subcutaneous adipose tissue volume (P = 0.045) were observed. No significant changes in glucose regulation or lipid profile occurred. Conclusion This study demonstrated the efficacy and safety of low-dose TH therapy for NAFLD in men. TH or TH analogs may be beneficial for this condition.

Visceral adipose tissue tracks more closely with metabolic dysfunction than intrahepatic triglyceride in non-diabetic lean Asians

Increased visceral adipose tissue (VAT) and intrahepatic triglyceride (IHTG) are important risk factors for the development of type 2 diabetes in subjects with obesity. The relative contribution of these ectopic fat depots to cardiometabolic risk differs between populations, depends on the degree of obesity and the level of cardiorespiratory fitness, and is difficult to dissect because VAT and IHTG typically covary. The aim of this study was to evaluate the effect of an isolated increase in VAT or IHTG on insulin sensitivity and insulin secretion in apparently healthy normal-weight Asian subjects. Total body fat (dual X-ray absorptiometry), VAT and IHTG (magnetic resonance), insulin sensitivity (4-h hyperinsulinemic-euglycemic clamp), beta cell responsivity and insulin secretion rate (3-h mixed meal with mathematical modeling), and cardiorespiratory fitness (maximal oxygen consumption [V̇o2max]) were evaluated in groups of lean subjects with low or high VAT (687 ± 94 vs. 1,279 ± 197 ml, matched for IHTG; n = 13 each) and low or high IHTG (1.7 ± 0.3 vs. 6.7 ± 2.0%, matched for VAT; n = 15 each). All groups were matched for age, sex, total body fat, and V̇o2max. High-VAT subjects had ~25% lower insulin sensitivity, ~20%-40% greater beta cell responsivity and insulin secretion rate, ~35% greater fasting triglyceride concentration, and ~40% lower adiponectin concentration than low-VAT subjects (all P < 0.05). No differences were observed between low-IHTG and high-IHTG subjects. Accumulation of excess fat in the intra-abdominal area is more strongly associated with metabolic dysfunction than accumulation of liver fat in lean Asians without diabetes. NEW & NOTEWORTHY It is not known whether metabolic abnormalities in Asians without obesity track more closely with visceral or liver fat. We found an isolated increase in visceral fat was associated with reduced insulin sensitivity, greater insulin secretion, greater triglyceride, and lower adiponectin concentrations; no differences were observed with an isolated increase in liver fat. These results suggest that visceral fat is a better correlate of metabolic dysfunction than liver fat in Asians without obesity.

Assessment of Lipid and Metabolite Changes in Obese Calf Muscle Using Multi-Echo Echo-planar Correlated Spectroscopic Imaging

Obesity-related conditions including heart disease, stroke, and type 2 diabetes are leading causes of preventable death. Recent evidence suggests that altered myocellular lipid metabolism in obesity may lead to increased insulin resistance (IR) that predisposes to these disorders. To test the hypothesis that muscles rich in type I vs. type II muscle fibers would exhibit similar changes in intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) content in obesity, we utilized a new four-dimensional multi echo echo-planar correlated spectroscopic imaging technique that allows separate determination of IMCL and EMCL content in individual calf muscles in obese vs. normal healthy human subjects. Calf muscles were scanned in 32 obese and 11 healthy subjects using a 3T MRI/MRS scanner, and IR in the obese subjects was documented by glucose tolerance testing. In obese subjects, elevation of both IMCL and EMCL content was observed in the gastrocnemius and tibialis anterior muscles (with mixed type I and II fiber content), while a significant increase in only IMCL content (+48%, p < 0.001) was observed in the soleus muscle (predominantly type I fibers). These observations indicate unexpected differences in changes in myolipid metabolism in type I vs. type II rich muscle regions in obesity, perhaps related to IR, and warrant further investigation.