Jimmy D. Bell

Human gene for physical performance

A specific genetic factor that strongly influences human physical performance has not so far been reported, but here we show that a polymorphism in the gene encoding angiotensin-converting enzyme does just that. An ‘insertion’ allele of the gene is associated with elite endurance performance among high-altitude mountaineers. Also, after physical training, repetitive weight-lifting is improved eleven-fold in individuals homozygous for the ‘insertion’ allele compared with those homozygous for the ‘deletion’ allele.

Proton MR spectroscopy of intracranial tumours: in vivo and in vitro studies.

Proton magnetic resonance spectroscopy (1H MRS) was used to investigate intracranial tumours in vitro and in vivo. Biopsy specimens were studied from 47 patients, 11 of whom were also examined in vivo. Analysis was based on the signals from N-acetylaspartate (NAA), phosphocreatine plus creatine (Cr), choline-containing compounds (Cho), alanine (Ala), and lactate. Biopsy data from 26 astrocytomas showed that the NAA/Cr ratio differs significantly in all grades from its value in normal white matter and that the Cho/Cr ratio differs significantly in grade IV tumours from its value in the other grades. Meningiomas have an unusually high Ala/Cr ratio. Spectra obtained in vivo are consistent with in vitro results from the same patients, and their lactate signal provides additional information about abnormal metabolism. We conclude that 1H MRS has a clear role in the diagnosis and biochemical assessment of intracranial tumours and in the evaluation and monitoring of therapy.

Hepatic triglyceride content and its relation to body adiposity: a magnetic resonance imaging and proton magnetic resonance spectroscopy study

Background: Hepatic steatosis is associated with obesity and type II diabetes. Proton magnetic resonance spectroscopy (1H MRS) is a non-invasive method for measurement of tissue fat content, including intrahepatocellular lipids (IHCL) and intramyocellular lipids (IMCL). Patients and methods: We used 1H MRS and whole body magnetic resonance imaging (MRI) to assess the relationship between IHCL accumulation, total body adipose tissue (AT) content/distribution, and IMCL content in 11 subjects with biopsy proven hepatic steatosis and 23 normal volunteers. Results: IHCL signals were detectable in all subjects but were significantly greater in hepatic steatosis (geometric mean (GM) 11.5 (interquartile range (IQR) 7.0–39.0)) than in normal volunteers (GM 2.7 (IQR 0.7–9.3); p = 0.02). In the study group as a whole, IHCL levels were significantly greater in overweight compared with lean subjects (body mass index (BMI) >25 kg/m2 (n = 23): GM 7.7 (IQR 4.0–28.6) v BMI <25 kg/m2 (n = 11): GM 1.3 (IQR 0.3–3.6; p = 0.004)). There was a significant association between IHCL content and indices of overall obesity (expressed as a percentage of body weight) for total body fat (p = 0.001), total subcutaneous AT (p = 0.007), and central obesity (subcutaneous abdominal AT (p = 0.001) and intra-abdominal AT (p = 0.001)), after allowing for sex and age. No correlation between IHCL content and IMCL was observed. A significant correlation was observed between serum alanine aminotransferase and liver fat content (r = 0.57, p = 0.006). Conclusions: Our results suggest that hepatic steatosis appears to be closely related to body adiposity, especially central obesity. MRS may be a useful method for monitoring IHCL in future interventional studies.

The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism

Increased intake of dietary carbohydrate that is fermented in the colon by the microbiota has been reported to decrease body weight, although the mechanism remains unclear. Here we use in vivo11C-acetate and PET-CT scanning to show that colonic acetate crosses the blood–brain barrier and is taken up by the brain. Intraperitoneal acetate results in appetite suppression and hypothalamic neuronal activation patterning. We also show that acetate administration is associated with activation of acetyl-CoA carboxylase and changes in the expression profiles of regulatory neuropeptides that favour appetite suppression. Furthermore, we demonstrate through 13C high-resolution magic-angle-spinning that 13C acetate from fermentation of 13C-labelled carbohydrate in the colon increases hypothalamic 13C acetate above baseline levels. Hypothalamic 13C acetate regionally increases the 13C labelling of the glutamate–glutamine and GABA neuroglial cycles, with hypothalamic 13C lactate reaching higher levels than the ‘remaining brain’. These observations suggest that acetate has a direct role in central appetite regulation.

Altered adiposity after extremely preterm birth

The quantity and distribution of adipose tissue are markers of morbidity risk. The third trimester of human development is a period of rapid adipose tissue deposition. Preterm infants may be at risk of altered adiposity. We measured anthropometric indices and quantified total, subcutaneous, and intraabdominal adipose tissue volumes using whole-body magnetic resonance adipose tissue imaging in 38 infants born at <32 wk gestational age, when they reached term, and 29 term-born infants. The preterm infants at term were significantly lighter and shorter than the term-born infants, but there was no significant difference in head circumference SD score or total adiposity. The preterm infants had a highly significant decrease in subcutaneous adipose tissue and significantly increased intraabdominal adipose tissue. Accelerated postnatal weight gain was accompanied by increased total and subcutaneous adiposity. Illness severity was the principal determinant of increased intraabdominal adiposity. Our data provide evidence of causal pathways linking accelerated postnatal growth with increased total and subcutaneous adiposity, and illness severity with altered adipose tissue partitioning. We suggest that these observations may in part explain the associations between small size at birth and later disease. Preterm infants may be at risk in later life of metabolic complications through increased and aberrant adiposity.

Fasting biases brain reward systems towards high-calorie foods.

Nutritional state (e.g. fasted vs. fed) and different food stimuli (e.g. high‐calorie vs. low‐calorie, or appetizing vs. bland foods) are both recognized to change activity in brain reward systems. Using functional magnetic resonance imaging, we have studied the interaction between nutritional state and different food stimuli on brain food reward systems. We examined how blood oxygen level‐dependent activity within a priori regions of interest varied while viewing pictures of high‐calorie and low‐calorie foods. Pictures of non‐food household objects were included as control stimuli. During scanning, subjects rated the appeal of each picture. Twenty non‐obese healthy adults [body mass index 22.1 ± 0.5 kg/m2 (mean ± SEM), age range 19–35 years, 10 male] were scanned on two separate mornings between 11:00 and 12:00 h, once after eating a filling breakfast (‘fed’: 1.6 ± 0.1 h since breakfast), and once after an overnight fast but skipping breakfast (‘fasted’: 15.9 ± 0.3 h since supper) in a randomized cross‐over design. Fasting selectively increased activation to pictures of high‐calorie over low‐calorie foods in the ventral striatum, amygdala, anterior insula, and medial and lateral orbitofrontal cortex (OFC). Furthermore, fasting enhanced the subjective appeal of high‐calorie more than low‐calorie foods, and the change in appeal bias towards high‐calorie foods was positively correlated with medial and lateral OFC activation. These results demonstrate an interaction between homeostatic and hedonic aspects of feeding behaviour, with fasting biasing brain reward systems towards high‐calorie foods.

Angiotensin-converting-enzyme gene insertion/deletion polymorphism and response to physical training.

BACKGROUND The function of local renin-angiotensin systems in skeletal muscle and adipose tissue remains largely unknown. A polymorphism of the human angiotensin converting enzyme (ACE) gene has been identified in which the insertion (I) rather than deletion (D) allele is associated with lower ACE activity in body tissues and increased response to some aspects of physical training. We studied the association between the ACE gene insertion or deletion polymorphism and changes in body composition related to an intensive exercise programme, to investigate the metabolic effects of local human renin-angiotensin systems. METHODS We used three independent methods (bioimpedance, multiple skinfold-thickness assessment of whole-body composition, magnetic resonance imaging of the mid-thigh) to study changes in body composition in young male army recruits over 10 weeks of intensive physical training. FINDINGS Participants with the II genotype had a greater anabolic response than those with one or more D alleles for fat mass (0.55 vs -0.20 kg, p=0.04 by bioimpedance) and non-fat mass (1.31 vs -0.15 kg, p=0.01 by bioimpedance). Changes in body morphology with training measured by the other methods were also dependent on genotype. INTERPRETATION II genotype, as a marker of low ACE activity in body tissues, may conserve a positive energy balance during rigorous training, which suggests enhanced metabolic efficiency. This finding may explain some of the survival and functional benefits of therapy with ACE inhibitors.

The role of insulin receptor substrate 2 in hypothalamic and β cell function

Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in β cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and β cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced β cell mass. Overt diabetes did not ensue, because β cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced β cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in β cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis.

Relation of triglyceride stores in skeletal muscle cells to central obesity and insulin sensitivity in European and South Asian men

Aims/hypothesis. To compare the relation between intramyocellular lipid content, central obesity and insulin sensitivity in Europeans and South Asians. Methods. Cross-sectional study of 40 South Asian and European non-diabetic men matched for age and body mass index. We measured intramyocellular lipid by proton magnetic resonance spectroscopy of soleus muscle, insulin sensitivity by the short insulin tolerance test, per cent body fat by dual-energy x-ray absorptiometry and visceral fat by single-slice computed tomography of the abdomen. Results. South Asians compared with Europeans had a higher mean per cent body fat (26.8 % vs 22.5 %, p = 0.05) and lower insulin sensitivity (mean ± SEM 2.4 ± 0.2 vs 3.4 %/min ± 0.3, p = 0.013). Mean ( ± SEM) intramyocellular lipid content was higher in South Asians than in Europeans (72.1 ± 7.5 vs 53.6 ± 4.9 mmol/kg dry weight, p = 0.046). In Europeans intramyocellular lipid was correlated with per cent body fat (r = 0.50, p = 0.028), waist:hip ratio (r = 0.74, p < 0.001), visceral fat (r = 0.62, p = 0.004) and insulin sensitivity (r = –0.53, p = 0.016). In South Asians intramyocellular lipid was not significantly related to insulin sensitivity or obesity, and the strongest associations of insulin sensitivity were with fasting plasma triglyceride and waist:hip ratio. Conclusion/interpretation. The association of intramyocellular lipid with insulin sensitivity and obesity in Europeans is consistent with the hypothesis that muscle triglyceride mediates the effect of obesity on insulin sensitivity. The absence of a similar relation of insulin sensitivity to intramyocellular lipid in South Asians suggests that other mechanisms underlie the high insulin resistance observed in this group. [Diabetologia (1999) 42: 932–935]

Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults.

Objective The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults. Design To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults. Results Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group. Conclusions These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans. Trial registration number NCT00750438.