Relationships between Insulin Sensitivity and Measures of Body Fat in Asymptomatic Men and Women

Objective: To assess whether measures of body fat by DXA scanning can improve prediction of insulin sensitivity (S_I) beyond what is possible with traditional measures, such as BMI, waist circumference, and waist‐to‐hip ratio (WHR). Research Methods and Procedures: Frequently sampled intravenous glucose tolerance tests were performed in 256 asymptomatic non‐Hispanic white subjects from Rochester, MN (age 19‐60 years; 123 men and 133 women) to determine the S_I index by Bergman's minimal model technique. Height, weight, and waist and hip circumferences were measured for calculation of BMI and WHR; DXA was used to determine fat in the head, upper body, abdomen, and lower body. Linear regression was used to assess their relationships with S_I after sex stratification and adjustment for age. Results: After controlling for age, increases in traditional and DXA measures of fat were consistently associated with smaller declines in S_I among women than among men. In men, after controlling for age, all of the predictive information of S_I was provided by waist circumference (additional R² = 0.39, p < 0.001); none of the DXA measures improved the ability to predict S_I. In women, after adjustment for age, BMI, and WHR, the only DXA measure that improved the prediction of S_I was percentage head fat (additional R² = 0.03, p < 0.001). Discussion: Equivalent increases in most measures of body fat had lesser impact on S_I in women than in men. In both sexes, the predictive information provided by DXA measures is approximately equal to, but not additive to, that provided by simpler, traditional measures.     

Fatty acid-binding protein and its relation to fatty acid oxidation

A relation between fatty acid oxidation capacity and cytosolic FABP content was found in heart and various muscles of the rat. Other tissues do not show such a relation, since they are involved in more or other pathways of fatty acid metabolism. At postnatal development FABP content and fatty acid oxidation capacity rise concomitantly in heart and quadriceps muscle in contrast to in liver and kidney. A dietary fat content of 40 en. % increased only the FABP content of liver and adipose tissue. Peroxisomal proliferators increased fatty acid oxidation in both liver and kidney, but only the FABP content of liver, and had no effect on heart and skeletal muscle. The FABP content of muscle did not show adaptation to various conditions. Only it increased in fast-twitch muscles upon chronic electrostimulation and endurance training.     

Changes of glycogen content in liver,skeletal muscle,and heart from fasted rats

Glycogen content of white and red skeletal muscles, cardiac muscle, and liver was investigated in conditions where changes in plasma levels of non‐esterified fatty acids (NEFA) occur. The experiments were performed in fed and 12 and 48 h‐fasted rats. The animals were also submitted to swimming for 10 and 30 min. Glycogen content was also investigated in both pharmacologically induced low plasma NEFA levels fasted rats and pharmacologically induced high plasma NEFA levels fed rats. The participation of Akt and glycogen synthase kinase‐3 (GSK‐3) in the changes observed was investigated. Plasma levels of NEFA, glucose, and insulin were determined in all conditions. Fasting increased plasma NEFA levels and reduced glycogen content in the liver and skeletal muscles. However, an increase of glycogen content was observed in the heart under this condition. Akt and GSK‐3 phosphorylation was reduced during fasting in the liver and skeletal muscles but it remained unchanged in the heart. Our results suggest that in conditions of increased plasma NEFA levels, changes in insulin‐stimulated phosphorylation of Akt and GSK‐3 and glycogen content vary differently in liver, skeletal muscles, and heart. Akt and GSK‐3 phosphorylation and glycogen content are decreased in liver and skeletal muscles, but in the heart it remain unchanged (Akt and GSK‐3 phosphorylation) or increased (glycogen content) due to consistent increase of plasma NEFA levels. Copyright © 2009 John Wiley & Sons, Ltd.     

Blocking mitochondrial pyruvate import in brown adipocytes induces energy wasting via lipid cycling

Combined fatty acid esterification and lipolysis, termed lipid cycling, is an ATP‐consuming process that contributes to energy expenditure. Therefore, interventions that stimulate energy expenditure through lipid cycling are of great interest. Here we find that pharmacological and genetic inhibition of the mitochondrial pyruvate carrier (MPC) in brown adipocytes activates lipid cycling and energy expenditure, even in the absence of adrenergic stimulation. We show that the resulting increase in ATP demand elevates mitochondrial respiration coupled to ATP synthesis and fueled by lipid oxidation. We identify that glutamine consumption and the Malate‐Aspartate Shuttle are required for the increase in Energy Expenditure induced by MPC inhibition in Brown Adipocytes (MAShEEBA). We thus demonstrate that energy expenditure through enhanced lipid cycling can be activated in brown adipocytes by decreasing mitochondrial pyruvate availability. We present a new mechanism to increase energy expenditure and fat oxidation in brown adipocytes, which does not require adrenergic stimulation of mitochondrial uncoupling.     

Influence of Total vs. Visceral Fat on Insulin Action and Secretion in African American and White Children

Objective: To examine whether total body fat (FAT) in general or visceral fat (VFAT) in particular is associated with greater metabolic risk in white and African American children. Research Methods and Procedures: A total of 68 white and 51 African American children had measures of insulin sensitivity (Si) and acute insulin response (AIR) by a frequently sampled intravenous glucose tolerance test, total body fat by DXA and abdominal fat distribution (visceral vs. subcutaneous) by computed tomography. The influence of FAT and VFAT on insulin parameters were examined by comparing subgroups of children with high or low FAT vs. high or low VFAT and by multiple regression analysis. Results: In whites, fasting insulin, Si, and AIR were significantly influenced by FAT, but not VFAT (e.g., for Si, 9.8 ± 0.8 in low FAT vs. 4.6 ± 0.7 × 10^?4/min/[μIU/mL] in high FAT, p < 0.05; 6.8 ± 0.7 in low VFAT vs. 7.5 ± 0.8 × 10^?4/min/[μIU/mL] in high VFAT, p > 0.1). In African Americans, fasting insulin and Si were also primarily influenced by FAT (e.g., for Si, 4.9 ± 0.4 in low FAT vs. 2.8 ± 0.5 × 10^?4/min/[μIU/mL] in high FAT, p < 0.05) but not by VFAT, and there were no significant effects of either fat compartment on AIR. In multiple regression analysis, Si was significantly influenced by FAT (negative effect), ethnicity (lower in African Americans), and gender (lower in females), whereas fasting insulin was significantly influenced by VFAT (positive effect), ethnicity (higher in African Americans), and fat free mass (positive effect). Discussion: Body fat in general is the predominant factor influencing Si, but VFAT may have additional effects on fasting insulin. The lack of major effects of VFAT on Si in children may be explained by lower levels of VFAT or because VFAT affects aspects of whole body insulin action that are not measured by the minimal model.     

Insulin Sensitivity,Body Fat Distribution,and Family Diabetes History: The IRAS Family Study

Objectives : Markers of insulin resistance are often apparent in nondiabetic relatives of subjects with type 2 diabetes. Whether diabetes family history (FH) also predicts visceral fat accumulation and, if so, whether the increased insulin resistance in relatives of diabetic subjects occurs independently of visceral fat accumulation are not known. Research Methods and Procedures : To examine this issue, we studied the relationship of diabetes FH with insulin sensitivity and fat measures, measured by minimal model analysis and computed tomography, respectively, in families participating in the Insulin Resistance Atherosclerosis (IRAS) Family Study. FH scores were based on the diabetes status of the participants’ parents and older siblings. Results : FH scores were significantly correlated with reduced insulin sensitivity (p < 0.05) and increased subcutaneous (p < 0.05) and visceral (p < 0.05, San Antonio only) fat in families from San Antonio and Los Angeles but not in the leaner Hispanic families from San Luis Valley. There was no evidence for a stronger association of FH score with visceral fat accumulation than with subcutaneous fat or insulin resistance. Discussion : The absence of an association between FH score and insulin resistance/fat accumulation in San Luis Valley is consistent with the idea that the expression of transmitted diabetes genes may be suppressed in leaner, more physically active populations.     

Biology and pathological implications of brown adipose tissue: promises and caveats for the control of obesity and its associated complications

The discovery of metabolically active brown adipose tissue (BAT) in adult humans has fuelled the research of diverse aspects of this previously neglected tissue. BAT is solely present in mammals and its clearest physiological role is non‐shivering thermogenesis, owing to the capacity of brown adipocytes to dissipate metabolic energy as heat. Recently, a number of other possible functions have been proposed, including direct regulation of glucose and lipid homeostasis and the secretion of a number of factors with diverse regulatory actions. Herein, we review recent advances in general biological knowledge of BAT and discuss the possible implications of this tissue in human metabolic health. In particular, we confront the claimed thermogenic potential of BAT for human energy balance and body mass regulation, mostly based on animal studies, with the most recent quantifications of human BAT.     

Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis

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PEX11 promotes peroxisome division independently of peroxisome metabolism

The PEX11 peroxisomal membrane proteins are the only factors known to promote peroxisome division in multiple species. It has been proposed that PEX11 proteins have a direct role in peroxisomal fatty acid oxidation, and that they only affect peroxisome abundance indirectly. Here we show that PEX11 proteins are unique in their ability to promote peroxisome division, and that PEX11 overexpression promotes peroxisome division in the absence of peroxisomal metabolic activity. We also observed that mouse cells lacking PEX11beta display reduced peroxisome abundance, even in the absence of peroxisomal metabolic substrates, and that PEX11beta(-/-) mice are partially deficient in two distinct peroxisomal metabolic pathways, ether lipid synthesis and very long chain fatty acid oxidation. Based on these and other observations, we propose that PEX11 proteins act directly in peroxisome division, and that their loss has indirect effects on peroxisome metabolism.     

Medium‐Chain Oil Reduces Fat Mass and Down‐regulates Expression of Adipogenic Genes in Rats

Objective: To test the hypothesis that adipose tissue could be one of the primary targets through which medium‐chain fatty acids (MCFAs) exert their metabolic influence. Research Methods and Procedures: Sprague‐Dawley rats were fed a control high‐fat diet compared with an isocaloric diet rich in medium‐chain triglycerides (MCTs). We determined the effects of MCTs on body fat mass, plasma leptin and lipid levels, acyl chain composition of adipose triglycerides and phospholipids, adipose tissue lipoprotein lipase activity, and the expression of key adipogenic genes. Tissue triglyceride content was measured in heart and gastrocnemius muscle, and whole body insulin sensitivity and glucose tolerance were also measured. The effects of MCFAs on lipoprotein lipase activity and adipogenic gene expression were also assessed in vitro using cultured adipose tissue explants or 3T3‐L1 adipocytes. Results: MCT‐fed animals had smaller fat pads, and they contained a considerable amount of MCFAs in both triglycerides and phospholipids. A number of key adipogenic genes were down‐regulated, including peroxisome proliferator activated receptor γ and CCAAT/enhancer binding protein α and their downstream metabolic target genes. We also found reduced adipose tissue lipoprotein lipase activity and improved insulin sensitivity and glucose tolerance in MCT‐fed animals. Analogous effects of MCFAs on adipogenic genes were found in cultured rat adipose tissue explants and 3T3‐L1 adipocytes. Discussion: These results suggest that direct inhibitory effects of MCFAs on adiposity may play an important role in the regulation of body fat development.     

Effects of Different Dietary Fat Types on Postprandial Appetite and Energy Expenditure

Objective: Observational studies suggest that monounsaturated (MUFA) and trans fatty acids (TRANS) are more fattening than polyunsaturated fatty acids (PUFA). Therefore, the aim of this study was to investigate the acute effect of intake of PUFA, MUFA, or TRANS on appetite and energy expenditure (EE). Research Methods and Procedures: Three test meals were randomly given in a cross‐over design to 19 overweight (BMI: 26.8 ± 0.4 kg/m²), young (25.2 ± 0.7 years) men. The fat‐rich breakfasts (0.8 g fat/kg body weight, 60% energy from fat) varied only in the source of C:18‐fat. EE was measured continuously in a respiration chamber, and appetite sensations were rated by visual analog scales before and every 30 minutes, for 5 hours, after the meal. After 5 hours, an ad libitum meal was served, and energy intake was registered. Sensory evaluations of all meals were given using visual analog scales. Data were analyzed by two‐way ANOVA. Results: There were no differences in basal or postprandial values of appetite ratings and EE, in subsequent ad libitum energy intake, or in the sensory evaluation of the test meals among the 3 test days. Discussion: Giving acutely large amounts of MUFA, PUFA, or TRANS did not impose any differences in appetite and EE in overweight humans. However, studies with extended protocols and other subject groups are warranted to investigate the long‐term effect of dietary fat quality on the regulation of energy balance and body weight.     

Mitochondrial dysfunction in non-alcoholic fatty liver disease and insulin resistance: Cause or consequence?

Abstract

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of the metabolic syndrome and refers to a spectrum of disorders ranging from steatosis to steatohepatitis, a disease stage characterized by inflammation, fibrosis, cell death and insulin resistance (IR). Due to its association with obesity and IR the impact of NAFLD is growing worldwide. Consistent with the role of mitochondria in fatty acid (FA) metabolism, impaired mitochondrial function is thought to contribute to NAFLD and IR. Indeed, mitochondrial dysfunction and impaired mitochondrial respiratory chain have been described in patients with non-alcoholic steatohepatitis and skeletal muscle of obese patients. However, recent data have provided evidence that pharmacological and genetic models of mitochondrial impairment with reduced electron transport stimulate insulin sensitivity and protect against diet-induced obesity, hepatosteatosis and IR. These beneficial metabolic effects of impaired mitochondrial oxidative phosphorylation may be related not only to the reduction of reactive oxygen species production that regulate insulin signaling but also to decreased mitochondrial FA overload that generate specific metabolites derived from incomplete FA oxidation (FAO) in the TCA cycle. In line with the Randle cycle, reduced mitochondrial FAO rates may alleviate the repression on glucose metabolism in obesity. In addition, the redox paradox in insulin signaling and the delicate mitochondrial antioxidant balance in steatohepatitis add another level of complexity to the role of mitochondria in NAFLD and IR. Thus, better understanding the role of mitochondria in FA metabolism and glucose homeostasis may provide novel strategies for the treatment of NAFLD and IR.     

Pathophysiology and Pathogenesis of Visceral Fat Obesity

Based on the analysis of fat distribution by computed tomography (CT) scans, the classification scheme for obesity should include visceral fat obesity in which fat accumulation is predominant in the intra-abdominal cavity. Obese subjects with visceral fat accumulation more frequently demonstrate impairment of glucose and lipid metabolism than those with subcutaneous fat accumulation. We have shown that visceral fat obesity is present in almost 90% of obese patients with ischemic heart disease. Even in non-obese subjects, visceral fat accumulation is correlated with glucose intolerance, hyperlipidemia and hypertension. Forty percent of non-obese subjects with coronary artery disease (CAD) had increased visceral fat. In non-obese subjects, visceral fat area assessed by abdominal CT at the level of the umbilicus correlates with metabolic risk factors, whereas in obese subjects the visceral fat area to subcutaneous fat area ratio provides a more significant correlation. From clinical and basic investigations, aging, sex hormones, excess intake of sucrose and lack of physical exercise have been suggested to be determinants for visceral fat accumulation. Since intra-abdominal fat (mesenteric and omentum fat) has been shown to have high activities of both lipogenesis and lipolysis, its accumulation can induce high levels of free fatty acids, a product of lipolysis, in portal circulation which go into the liver. Excess free fatty acids may cause the enhancement of lipid synthesis and gluconeo genesis as well as insulin resistance, resulting in hyperlipidemia, glucose intolerance and hypertension and finally atherosclerosis. Thus we propose a disease entity, visceral fat syndrome, which may increase susceptibility to atherosclerosis due to multiple risk factors induced by visceral fat accumulation.     

CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance

Mutations of Comparative Gene Identification-58 (CGI-58) in humans cause triglyceride (TG) accumulation in multiple tissues. Mice genetically lacking CGI-58 die shortly after birth due to a skin barrier defect. To study the role of CGI-58 in integrated lipid and energy metabolism, we utilized antisense oligonucleotides (ASOs) to inhibit CGI-58 expression in adult mice. Treatment with two distinct CGI-58-targeting ASOs resulted in ∼80–95% knockdown of CGI-58 protein expression in both liver and white adipose tissue. In chow-fed mice, ASO-mediated depletion of CGI-58 did not alter weight gain, plasma TG, or plasma glucose, yet raised hepatic TG levels ∼4-fold. When challenged with a high-fat diet (HFD), CGI-58 ASO-treated mice were protected against diet-induced obesity, but their hepatic contents of TG, diacylglycerols, and ceramides were all elevated, and intriguingly, their hepatic phosphatidylglycerol content was increased by 10-fold. These hepatic lipid alterations were associated with significant decreases in hepatic TG hydrolase activity, hepatic lipoprotein-TG secretion, and plasma concentrations of ketones, nonesterified fatty acids, and insulin. Additionally, HFD-fed CGI-58 ASO-treated mice were more glucose tolerant and insulin sensitive. Collectively, this work demonstrates that CGI-58 plays a critical role in limiting hepatic steatosis and maintaining hepatic glycerophospholipid homeostasis and has unmasked an unexpected role for CGI-58 in promoting HFD-induced obesity and insulin resistance.     

Mfn2 deletion in brown adipose tissue protects from insulin resistance and impairs thermogenesis

BAT‐controlled thermogenic activity is thought to be required for its capacity to prevent the development of insulin resistance. This hypothesis predicts that mediators of thermogenesis may help prevent diet‐induced insulin resistance. We report that the mitochondrial fusion protein Mitofusin 2 (Mfn2) in BAT is essential for cold‐stimulated thermogenesis, but promotes insulin resistance in obese mice. Mfn2 deletion in mice through Ucp1‐cre (BAT‐Mfn2‐KO) causes BAT lipohypertrophy and cold intolerance. Surprisingly however, deletion of Mfn2 in mice fed a high fat diet (HFD) results in improved insulin sensitivity and resistance to obesity, while impaired cold‐stimulated thermogenesis is maintained. Improvement in insulin sensitivity is associated with a gender‐specific remodeling of BAT mitochondrial function. In females, BAT mitochondria increase their efficiency for ATP‐synthesizing fat oxidation, whereas in BAT from males, complex I‐driven respiration is decreased and glycolytic capacity is increased. Thus, BAT adaptation to obesity is regulated by Mfn2 and with BAT‐Mfn2 absent, BAT contribution to prevention of insulin resistance is independent and inversely correlated to whole‐body cold‐stimulated thermogenesis.     

Body Weight Loss and Weight Maintenance in Relation to Habitual Caffeine Intake and Green Tea Supplementation

Objective: Investigation of the effect of a green tea‐caffeine mixture on weight maintenance after body weight loss in moderately obese subjects in relation to habitual caffeine intake. Research Methods and Procedures: A randomized placebo‐controlled double blind parallel trial in 76 overweight and moderately obese subjects, (BMI, 27.5 ± 2.7 kg/m²) matched for sex, age, BMI, height, body mass, and habitual caffeine intake was conducted. A very low energy diet intervention during 4 weeks was followed by 3 months of weight maintenance (WM); during the WM period, the subjects received a green tea‐caffeine mixture (270 mg epigallocatechin gallate + 150 mg caffeine per day) or placebo. Results: Subjects lost 5.9 ±1.8 (SD) kg (7.0 ± 2.1%) of body weight (p < 0.001). At baseline, satiety was positively, and in women, leptin was inversely, related to subjects’ habitual caffeine consumption (p < 0.01). High caffeine consumers reduced weight, fat mass, and waist circumference more than low caffeine consumers; resting energy expenditure was reduced less and respiratory quotient was reduced more during weight loss (p < 0.01). In the low caffeine consumers, during WM, green tea still reduced body weight, waist, respiratory quotient and body fat, whereas resting energy expenditure was increased compared with a restoration of these variables with placebo (p < 0.01). In the high caffeine consumers, no effects of the green tea‐caffeine mixture were observed during WM. Discussion: High caffeine intake was associated with weight loss through thermogenesis and fat oxidation and with suppressed leptin in women. In habitual low caffeine consumers, the green tea‐caffeine mixture improved WM, partly through thermogenesis and fat oxidation.     

Skeletal Muscle Metabolism and Body Fat Content in Men and Women

The purpose of the present study was to verify the relationships between indicators of body Eat content and specific characteristics of skeletal muscle in a large sample of men and women. Six skinfold thicknesses (σ6S) and maximal oxygen uptake (VO₂ max) were measured in 348 Caucasian subjects (149 women and 199 men). Fiber type proportions (type I, type IIA, and type IIB) and activity levels of marker enzymes for the Krebs cycle (malate dehydrogenase, MDH) and for the fatty acid oxidation (3-hydroxya-cyl CoA dehydrogenase, HADH) pathways were determined in vastus lateralis muscle samples. No significant correlation was found between fiber type proportions and σ6S. Significant and negative correlations were, however, obtained in both genders between the σ6S and MDH enzyme activity (r = ?0.23; p<0.01), but not between the σ6S and HADH enzyme activity. When individuals with low and high amount of subcutaneous fat but paired for VO₂max were compared, vastus lateralis of fat men exhibited the same proportion of type I fiber (38.6 ± 10.3 vs 38.5 ± 13.4 %) and HADH activity level (3.43 ± 1.05 vs. 334 ± 0.81 U/g), but had about 20% less MDH enzyme activity than vastus lateralis of leaner men (158 ± 35 vs. 198 ± 43 U/g;p<0.05). No difference was found in any of these muscle phenotypes when comparisons were made between women with low and high amount of subcutaneous fat but also paired for VO₂max. Moreover, no relations were observed between skeletal muscle fiber type proportion or metabolic markers with relative subcutaneous fat distribution. In conclusion, these results indicate that the proportion of fiber type of skeletal muscle is not a determinant of body fat content or fat distribution in men and women. However, the results of the present study suggest, at least in men, that a low oxidative capacity of skeletal muscle, undetected by muscle fiber typing, is associated with an augmented body fat content.