Selective reduction in body fat mass and plasma leptin induced by angiotensin-converting enzyme inhibition in rats

Objective: There is emerging evidence that angiotensin stimulates adipocyte differentiation and lipogenesis. This study tested the hypothesis that inhibition of angiotensin II by treatment with an angiotensin-converting enzyme inhibitor, perindopril, would reduce fat mass in rats. Design: After a 12-day baseline, rats were divided into two groups: one was untreated and the other received perindopril (1.2 mg kg⁻¹ per day) in drinking water for 26 days.Subjects: In total, 16 male Sprague–Dawley rats aged 10 weeks at the start of the study. Measurements: Plasma leptin was measured in samples collected at baseline, half-way through and at the end of treatment. Body weight, food and water intake were measured daily throughout the experiment. Body fat mass, bone and lean mass were determined by dual energy X-ray absorptiometry (DEXA) at the end of the treatment period. Results: Daily food intake was the same in both groups throughout the study. By the end of treatment, animals receiving perindopril showed a modest reduction in weight gain relative to the untreated animals (62.4±5.0 g vs 73.0±4.0 g; P<0.05). DEXA analysis showed that body composition was greatly altered and the perindopril-treated group had 26% less body fat mass than the untreated group (61.0±5.2 g vs 44.4±4.2 g; P<0.01). The reduction in body fat mass was correlated with reductions in the weight of both the epididymal and retroperitoneal fat pads (P<0.001). Similarly, plasma leptin was reduced by perindopril treatment (4.64±0.56 ng ml⁻¹) compared to the untreated group (8.27±1.03 ng ml⁻¹; P<0.001). In contrast, there were no differences in lean or bone mass between the two groups.Conclusion: Oral treatment with perindopril selectively reduced body fat mass without influencing daily food intake. In contrast, there were no differences in lean or bone mass between the two groups

Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance

In addition to its role in the storage of fat, adipose tissue acts as an endocrine organ, and it contains a functional renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) plays a key role in the RAS by converting angiotensin I to the bioactive peptide angiotensin II (Ang II). In the present study, the effect of targeting the RAS in body energy homeostasis and glucose tolerance was determined in homozygous mice in which the gene for ACE had been deleted (ACE^-/-) and compared with wild-type littermates. Compared with wild-type littermates, ACE^-/- mice had lower body weight and a lower proportion of body fat, especially in the abdomen. ACE^-/- mice had greater fed-state total energy expenditure (TEE) and resting energy expenditure (REE) than wild-type littermates. There were pronounced increases in gene expression of enzymes related to lipolysis and fatty acid oxidation (lipoprotein lipase, carnitine palmitoyl transferase, long-chain acetyl CoA dehydrogenase) in the liver of ACE^-/- mice and also lower plasma leptin. In contrast, no differences were detected in daily food intake, activity, fed-state plasma lipids, or proportion of fat excrete in fecal matter. In conclusion, the reduction in ACE activity is associated with a decreased accumulation of body fat, especially in abdominal fat depots. The decreased body fat in ACE^-/- mice is independent of food intake and appears to be due to a high energy expenditure related to increased metabolism of fatty acids in the liver, with the additional effect of increased glucose tolerance.

Overweight children have a greater proportion of fat mass relative to muscle mass in the upper limbs than in the lower limbs : implications for bone strength at the distal forearm

Background: The influence of adiposity on upper-limb bone strength has rarely been studied in children, despite the high incidence of forearm fractures in this population.

Objective: The objective was to compare the influence of muscle and fat tissues on bone strength between the upper and lower limbs in prepubertal children.

Design: Bone mineral content, total bone cross-sectional area, cortical bone area (CoA), cortical thickness (CoTh) at the radius and tibia (4% and 66%, respectively), trabecular density (TrD), bone strength index (4% sites), cortical density (CoD), stress-strain index, and muscle and fat areas (66% sites) were measured by using peripheral quantitative computed tomography in 427 children (206 boys) aged 7–10 y.

Results: Overweight children (n = 93) had greater values for bone variables (0.3–1.3 SD; P < 0.0001) than did their normal-weight peers, except for CoD 66% and CoTh 4%. The between-group differences were 21–87% greater at the tibia than at the radius. After adjustment for muscle cross-sectional area, TrD 4%, bone mineral content, CoA, and CoTh 66% at the tibia remained greater in overweight children, whereas at the distal radius total bone cross-sectional area and CoTh were smaller in overweight children (P < 0.05). Overweight children had a greater fat-muscle ratio than did normal-weight children, particularly in the forearm (92 ± 28% compared with 57 ± 17%). Fat-muscle ratio correlated negatively with all bone variables, except for TrD and CoD, after adjustment for body weight (r = −0.17 to −0.54; P < 0.0001).

Conclusions: Overweight children had stronger bones than did their normal-weight peers, largely because of greater muscle size. However, the overweight children had a high proportion of fat relative to muscle in the forearm, which is associated with reduced bone strength.

Genetic variation in SH3-domain GRB2-like (endophilin)-interacting protein 1 has a major impact on fat mass

Objective:

The SH3-domain GRB2-like (endophilin)-interacting protein 1 (SGIP1) gene has been shown to be differentially expressed in the hypothalamus of lean versus obese Israeli sand rats (Psammomys obesus), and is suspected of having a role in regulating food intake. The purpose of this study was to assess the role of genetic variation in SGIP1 in human disease.
Subjects:

We performed single-nucleotide polymorphism (SNP) genotyping in a large family pedigree cohort from the island of Mauritius. The Mauritius Family Study (MFS) consists of 400 individuals from 24 Indo-Mauritian families recruited from the genetically homogeneous population of Mauritius. We measured markers of the metabolic syndrome, including diabetes and obesity-related phenotypes such as fasting plasma glucose, waist:hip ratio, body mass index and fat mass.
Results:

Statistical genetic analysis revealed associations between SGIP1 polymorphisms and fat mass (in kilograms) as measured by bioimpedance. SNP genotyping identified associations between several genetic variants and fat mass, with the strongest association for rs2146905 (P=4.7 × 10−5). A strong allelic effect was noted for several SNPs where fat mass was reduced by up to 9.4% for individuals homozygous for the minor allele.
Conclusions:

Our results show association between genetic variants in SGIP1 and fat mass. We provide evidence that variation in SGIP1 is a potentially important determinant of obesity-related traits in humans.

Influence of age and gender on fat mass, fat-free mass and skeletal muscle mass among Australian adults: the Australian diabetes, obesity and lifestyle study (AUSDIAB)

Background
Bioelectrical impedance (BIA) represents a simple, inexpensive and non-invasive method that is often used to assess fat-mass (FM) and fat-free mass (FFM) in large population-based cohorts.

Objective
The aim of this study was to describe the reference ranges and examine the influence of age and gender on FM, FFM and skeletal muscle mass (SMM) as well as height-adjusted estimates of FM [fat mass index (FMI)], FFM [fat-free mass index (FFMI)] and SMM [SMM index (SMI)] in a national, population-based cohort of Australian adults.

Design and Participants
The analytical sample included a total of 8,582 adults aged 25–91 years of Europid origin with complete data involved in the cross-sectional 1999–2000 Australian, Diabetes, Obesity and Lifestyle (AusDiab) Study.

Measurements
Bioelectrical impedance analysis was used to examine components of body composition. Demographic information was derived from a household interview.

Results
For both genders, FFM, SMM and SMI decreased linearly from the age of 25 years, with the exception that in men SMI was not related to age and FFM peaked at age 38 years before declining thereafter. The relative loss from peak values to ≥75 years in FFM (6–8%) and SMM (11–15%) was similar between men and women. For FM and FMI, there was a curvilinear relationship with age in both genders, but peak values were detected 6–7 years later in women with a similar relative loss thereafter. For FFMI there was no change with age in men and a modest increase in women.

Conclusion
In Australian adults there is heterogeneity in the age of onset, pattern and magnitude of changes in the different measures of muscle and fat mass derived from BIA, but overall the agerelated losses were similar between men and women.

Interleukin-6 and tumor necrosis factor-α are not increased in patients with type 2 diabetes: Evidence that plasma interleukin-6 is related to fat mass and not insulin responsiveness

Aims/hypothesis. Our aim was to examine the possible direct relationship of interleukin-6 and TNFα with insulin sensitivity in humans. Methods. We carried out two series of euglycaemic-hyperinsulinaemic clamp experiments. In the first (CLAMP1), skeletal muscle mRNA expression and plasma concentrations of IL-6 and TNFα were examined in patients with Type 2 diabetes (n=6), subjects matched for age (n=6), and young healthy (n=11) control subjects during a 120-min supra-physiological hyperinsulinaemic (40 mU·m -2·min-1) euglycaemic clamp. In the second series of experiments (CLAMP2), patients with Type 2 diabetes (n=6) and subjects matched for age (n=7) were studied during a 240-min high-physiological hyperinsulinaemic (7 mU·m-2·min-1) euglycaemic clamp, during which arterial and venous (femoral and subclavian) blood samples were measured for IL-6 and TNFα flux. Results. In both experiments the glucose infusion rate in the patients was markedly lower than that in the other groups. In CLAMP1, basal skeletal muscle IL-6 and TNFα mRNA were the same in all groups. They were not affected by insulin and they were not related to the glucose infusion rate. In CLAMP2, neither cytokine was released from the arm or leg during insulin stimulation in either group. In both experiments plasma concentrations of these cytokines were similar in the patients and in the control subjects, although in CLAMP1 the young healthy control group had lower (p<0.05) plasma IL-6 concentrations. Using data from all subjects, a strong positive correlation (r=0.85; p<0.00001) was observed between basal plasma IL-6 and BMI. Conversely, a negative relationship (r=-0.345; p<0.05) was found between basal plasma TNFα and BMI, although this was not significant when corrected for BMI. When corrected for BMI, no relationship was observed between either basal plasma IL-6 or TNFα and GIR. Conclusions/interpretation. These data show that the increased circulating IL-6 concentrations seen in patients with Type 2 diabetes are strongly related to fat mass and not insulin responsiveness, and suggest that neither IL-6 nor TNFα are indicative of insulin resistance.

Prognostic value of fat mass and skeletal muscle mass determined by computed tomography in patients who underwent transcatheter aortic valve implantation

Body composition (fat mass [FM] and skeletal muscle mass [SMM]) predicts clinical outcomes. In particular, loss of SMM (sarcopenia) is associated with frailty and mortality. There are no data on the prevalence and impact of FM and SMM in patients undergoing transcatheter aortic valve implantation (TAVI). The objective of this study is to determine body composition from pre-TAVI computed tomography (CT) and evaluate its association with clinical outcomes in patients who underwent TAVI. A total of 460 patients (mean age 81 ± 8 years, men: 51%) were included. Pre-TAVI CTs of the aorto-ilio-femoral axis were analyzed for FM and SMM cross-sectional area at the level of the third lumbar vertebrae (L3). Regression equations correlating cross-sectional area at L3 to total body FM and SMM were used to determine prevalence of sarcopenia, obesity, and sarcopenic obesity in patients (64%, 65%, and 46%, respectively). Most TAVI procedures were performed through a transfemoral approach (59%) using a balloon-expandable valve (94%). The 30-day and mid-term (median 12 months [interquartile range 6 to 27]) mortality rates were 6.1% and 29.6%, respectively. FM had no association with clinical outcomes, but sarcopenia predicted cumulative mortality (hazard ratio 1.55, 95% confidence interval 1.02 to 2.36, p = 0.04). In conclusion, body composition analysis from pre-TAVI CT is feasible. Sarcopenia, obesity, and sarcopenic obesity are prevalent in the TAVI population, with sarcopenia predictive of cumulative mortality.

Fat mass- and obesity-associated genotype, dietary intakes and anthropometric measures in European adults: the Food4Me study

The interplay between the fat mass- and obesity-associated (FTO) gene variants and diet has been implicated in the development of obesity. The aim of the present analysis was to investigate associations between FTO genotype, dietary intakes and anthropometrics among European adults. Participants in the Food4Me randomised controlled trial were genotyped for FTO genotype (rs9939609) and their dietary intakes, and diet quality scores (Healthy Eating Index and PREDIMED-based Mediterranean diet score) were estimated from FFQ. Relationships between FTO genotype, diet and anthropometrics (weight, waist circumference (WC) and BMI) were evaluated at baseline. European adults with the FTO risk genotype had greater WC (AA v. TT: +1·4 cm; P=0·003) and BMI (+0·9 kg/m2; P=0·001) than individuals with no risk alleles. Subjects with the lowest fried food consumption and two copies of the FTO risk variant had on average 1·4 kg/m2 greater BMI (Ptrend=0·028) and 3·1 cm greater WC (Ptrend=0·045) compared with individuals with no copies of the risk allele and with the lowest fried food consumption. However, there was no evidence of interactions between FTO genotype and dietary intakes on BMI and WC, and thus further research is required to confirm or refute these findings.

Fat mass is associated with foot pain in men: the Geelong osteoporosis study

OBJECTIVE: Foot pain is a common complaint in adults. Evidence suggests that body composition is involved in the development of foot pain. However, whether this is the case in men remains unclear because previous studies mainly examined women. The aim of this cross-sectional study was to determine the relationship between body composition and foot pain in men while accounting for important risk factors. METHODS: Among 978 men (median age 60 yrs, range 24-98) from the Geelong Osteoporosis Study who participated in a followup study in 2006 to 2011, 796 provided responses to questions on health status and foot pain. Foot pain was determined using the Manchester Foot Pain and Disability Index, and body composition was measured using dual-energy x-ray absorptiometry. RESULTS: Of the 796 respondents, 177 (22%) had foot pain. Risk factors for foot pain were age (OR 1.03, 95% CI 1.02-1.04), self-reported depression (OR 2.05, 95% CI 1.30-3.20), decreased mobility (OR 1.54, 95% CI 1.05-2.24), and lower education (OR 1.47, 95% CI 1.03-2.09). Foot pain was associated with body mass index (OR 1.05, 95% CI 1.00-1.10), fat mass (OR 1.02, 95% CI 1.03-1.05), and fat mass index (OR 1.08, 95% CI 1.01-1.15), but not fat-free mass (OR 1.01, 95% CI 0.98-1.04) or fat-free mass index (OR 1.05, 95% CI 0.95-1.15) after appropriate adjustments were made. CONCLUSION: Fat mass is associated with foot pain in men. These findings complement those in studies that have mainly examined women, and provide further evidence for the relationship between obesity and foot pain.

Prevalence of obesity and the relationship between the body mass index and body fat : cross-sectional, population-based data

Background: Anthropometric measures such as the body mass index (BMI) and waist circumference are widely used as convenient indices of adiposity, yet there are limitations in their estimates of body fat. We aimed to determine the prevalence of obesity using criteria based on the BMI and waist circumference, and to examine the relationship between the BMI and body fat.

Methodology/Principal Findings: This population-based, cross-sectional study was conducted as part of the Geelong Osteoporosis Study. A random sample of 1,467 men and 1,076 women aged 20–96 years was assessed 2001–2008. Overweight and obesity were identified according to BMI (overweight 25.0–29.9 kg/m2; obesity $30.0 kg/m2) and waist circumference (overweight men 94.0–101.9 cm; women 80.0–87.9 cm; obesity men $102.0 cm, women $88.0 cm); body fat mass was assessed using dual energy X-ray absorptiometry; height and weight were measured and lifestyle factors documented by self-report. According to the BMI, 45.1% (95%CI 42.4–47.9) of men and 30.2% (95%CI 27.4–33.0) of women were overweight and a further 20.2% (95%CI 18.0–22.4) of men and 28.6% (95%CI 25.8–31.3) of women were obese. Using waist circumference, 27.5% (95%CI 25.1–30.0) of men and 23.3% (95%CI 20.8–25.9) of women were overweight, and 29.3% (95%CI 26.9–31.7) of men and 44.1% (95%CI 41.2–47.1) of women, obese. Both criteria indicate that approximately 60% of the population exceeded recommended thresholds for healthy body habitus. There was no consistent pattern apparent between BMI and energy intake. Compared with women, BMI overestimated adiposity in men, whose excess weight was largely attributable to muscular body builds and greater bone mass. BMI also underestimated adiposity in the elderly. Regression models including gender, age and BMI explained 0.825 of the variance in percent body fat.

Conclusions/Significance: As the BMI does not account for differences in body composition, we suggest that gender- and age-specific thresholds should be considered when the BMI is used to indicate adiposity.

Calpain 3 gene expression in skeletal muscle is associated with body fat content and measures of insulin resistance

OBJECTIVE: To investigate whether skeletal muscle gene expression of calpain 3 is related to obesity and insulin resistance.

DESIGN: Cross-sectional studies in 27 non-diabetic human subjects and in Psammomys obesus, a polygenic animal model of obesity and type 2 diabetes.

MEASUREMENTS: Expression of CAPN3 in skeletal muscle was measured using Taqman fluorogenic PCR. In the human subjects, body composition was assessed by DEXA and insulin sensitivity was measured by euglycemic-hyperinsulinemic clamp. In Psammomys obesus, body composition was determined by carcass analysis, and substrate oxidation rates, physical activity and energy expenditure were measured by whole-body indirect calorimetry.

RESULTS: In human subjects, calpain 3 gene expression was negatively correlated with total (P=0.022) and central abdominal fat mass (P=0.034), and with blood glucose concentration in non-obese subjects (P=0.017). In Psammomys obesus, calpain 3 gene expression was negatively correlated with circulating glucose (P=0.013) and insulin (P=0.034), and with body fat mass (P=0.049). Indirect calorimetry revealed associations between calpain 3 gene expression and carbohydrate oxidation (P=0.009) and energy expenditure (P=0.013).

CONCLUSION/INTERPRETATION: Lower levels of expression of calpain 3 in skeletal muscle were associated with reduced carbohydrate oxidation and elevated circulating glucose and insulin concentrations, and also with increased body fat and in particular abdominal fat. Therefore, reduced expression of calpain 3 in both humans and Psammomys obesus was associated with phenotypes related to obesity and insulin resistance.

Does high-intensity resistance training maintain bone mass during moderate weight loss in older overweight adults with type 2 diabetes?

The aim was to investigate whether the addition of supervised high intensity progressive resistance training to a moderate weight loss program (RT+WLoss) could maintain bone mineral density (BMD) and lean mass compared to moderate weight loss (WLoss) alone in older overweight adults with type 2 diabetes. We also investigated whether any benefits derived from a supervised RT program could be sustained through an additional home-based program. This was a 12-month trial in which 36 sedentary, overweight adults aged 60 to 80 years with type 2 diabetes were randomized to either a supervised gymnasium-based RT+WLoss or WLoss program for 6 months (phase 1). Thereafter, all participants completed an additional 6-month home-based training without further dietary modification (phase 2). Total body and regional BMD and bone mineral content (BMC), fat mass (FM) and lean mass (LM) were assessed by DXA every 6 months. Diet, muscle strength (1-RM) and serum total testosterone, estradiol, SHBG, insulin and IGF-1 were measured every 3 months. No between group differences were detected for changes in any of the hormonal parameters at any measurement point. In phase 1, after 6 months of gymnasium-based training, weight and FM decreased similarly in both groups (P<0.01), but LM tended to increase in the RT+WLoss (n=16) relative to the WLoss (n=13) group [net difference (95% CI), 1.8% (0.2, 3.5), P<0.05]. Total body BMD and BMC remained unchanged in the RT+WLoss group, but decreased by 0.9 and 1.5%, respectively, in the WLoss group (interaction, P<0.05). Similar, though non-significant, changes were detected at the femoral neck and lumbar spine (L2-L4). In phase 2, after a further 6 months of home-based training, weight and FM increased significantly in both the RT+WLoss (n=14) and WLoss (n=12) group, but there were no significant changes in LM or total body or regional BMD or BMC in either group from 6 to 12 months. These results indicate that in older, overweight adults with type 2 diabetes, dietary modification should be combined with progressive resistance training to optimize the effects on body composition without having a negative effect on bone health.

Redistribution of glucose from skeletal muscle to adipose tissue during catch-up fat. A link between catch-up growth and later metabolic syndrome.

Catch-up growth, a risk factor for later obesity, type 2 diabetes, and cardiovascular diseases, is characterized by hyperinsulinemia and an accelerated rate for recovering fat mass, i.e., catch-up fat. To identify potential mechanisms in the link between hyperinsulinemia and catch-up fat during catch-up growth, we studied the in vivo action of insulin on glucose utilization in skeletal muscle and adipose tissue in a previously described rat model of weight recovery exhibiting catch-up fat caused by suppressed thermogenesis per se. To do this, we used euglycemic-hyperinsulinemic clamps associated with the labeled 2-deoxy-glucose technique. After 1 week of isocaloric refeeding, when body fat, circulating free fatty acids, or intramyocellular lipids in refed animals had not yet exceeded those of controls, insulin-stimulated glucose utilization in refed animals was lower in skeletal muscles (by 20–43%) but higher in white adipose tissues (by two- to threefold). Furthermore, fatty acid synthase activity was higher in adipose tissues from refed animals than from fed controls. These results suggest that suppressed thermogenesis for the purpose of sparing glucose for catch-up fat, via the coordinated induction of skeletal muscle insulin resistance and adipose tissue insulin hyperresponsiveness, might be a central event in the link between catch-up growth, hyperinsulinemia and risks for later metabolic syndrome.

Effects of resistance exercise and fortified milk on skeletal muscle mass, muscle size, and functional performance in middle-aged and older men: an 18-mo randomized controlled trial

Limited data have suggested that the consumption of fluid milk after resistance training (RT) may promote skeletal muscle hypertrophy. The aim of this study was to assess whether a milk-based nutritional supplement could enhance the effects of RT on muscle mass, size, strength, and function in middle-aged and older men. This was an 18-mo factorial design (randomized control trial) in which 180 healthy men aged 50–79 yr were allocated to the following groups: 1) exercise + fortified milk, 2) exercise, 3) fortified milk, or 4) control. Exercise consisted of progressive RT with weight-bearing impact exercise. Men assigned to the fortified milk consumed 400 ml/day of low-fat milk, providing an additional 836 kJ, 1000 mg calcium, 800 IU vitamin D3, and 13.2 g protein per day. Total body lean mass (LM) and fat mass (FM) (dual-energy X-ray absorptiometry), midfemur muscle cross-sectional area (CSA) (quantitative computed tomography), muscle strength, and physical function were assessed. After 18 mo, there was no significant exercise by fortified milk interaction for total body LM, muscle CSA, or any functional measure. However, main effect analyses revealed that exercise significantly improved muscle strength (∼20–52%, P < 0.001), LM (0.6 kg, P < 0.05), FM (−1.1 kg, P < 0.001), muscle CSA (1.8%, P < 0.001), and gait speed (11%, P < 0.05) relative to no exercise. There were no effects of the fortified milk on muscle size, strength, or function. In conclusion, the daily consumption of low-fat fortified milk does not enhance the effects of RT on skeletal muscle size, strength, or function in healthy middle-aged and older men with adequate energy and nutrient intakes.