E. Louise Thomas

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.

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.

Digenic inheritance of severe insulin resistance in a human pedigree

Impaired insulin action is a key feature of type 2 diabetes and is also found, to a more extreme degree, in familial syndromes of insulin resistance. Although inherited susceptibility to insulin resistance may involve the interplay of several genetic loci, no clear examples of interactions among genes have yet been reported. Here we describe a family in which five individuals with severe insulin resistance, but no unaffected family members, were doubly heterozygous with respect to frameshift/premature stop mutations in two unlinked genes, PPARG and PPP1R3A these encode peroxisome proliferator activated receptor γ, which is highly expressed in adipocytes, and protein phosphatase 1, regulatory subunit 3, the muscle-specific regulatory subunit of protein phosphatase 1, which are centrally involved in the regulation of carbohydrate and lipid metabolism, respectively. That mutant molecules primarily involved in either carbohydrate or lipid metabolism can combine to produce a phenotype of extreme insulin resistance provides a model of interactions among genes that may underlie common human metabolic disorders such as type 2 diabetes.

Improved glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists.

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective for obese patients with type 2 diabetes mellitus (T2DM) because they concomitantly target obesity and dysglycaemia. Considering the high prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with T2DM, we determined the impact of 6 months’ GLP-1 RA therapy on intrahepatic lipid (IHL) in obese, T2DM patients with hepatic steatosis, and evaluated the inter-relationship between changes in IHL with those in glycosylated haemoglobin (HbA1c), body weight, and volume of abdominal visceral and subcutaneous adipose tissue (VAT and SAT). We prospectively studied 25 (12 male) patients, age 50±10 years, BMI 38.4±5.6 kg/m2 (mean ± SD) with baseline IHL of 28.2% (16.5 to 43.1%) and HbA1c of 9.6% (7.9 to 10.7%) (median and interquartile range). Patients treated with metformin and sulphonylureas/DPP-IV inhibitors were given 6 months GLP-1 RA (exenatide, n = 19; liraglutide, n = 6). IHL was quantified by liver proton magnetic resonance spectroscopy (1H MRS) and VAT and SAT by whole body magnetic resonance imaging (MRI). Treatment was associated with mean weight loss of 5.0 kg (95% CI 3.5,6.5 kg), mean HbA1c reduction of 1·6% (17 mmol/mol) (0·8,2·4%) and a 42% relative reduction in IHL (−59.3, −16.5%). The relative reduction in IHL correlated with that in HbA1c (ρ = 0.49; p = 0.01) but was not significantly correlated with that in total body weight, VAT or SAT. The greatest IHL reduction occurred in individuals with highest pre-treatment levels. Mechanistic studies are needed to determine potential direct effects of GLP-1 RA on human liver lipid metabolism.

The missing risk: MRI and MRS phenotyping of abdominal adiposity and ectopic fat.

Individual compartments of abdominal adiposity and lipid content within the liver and muscle are differentially associated with metabolic risk factors, obesity and insulin resistance. Subjects with greater intra‐abdominal adipose tissue (IAAT) and hepatic fat than predicted by clinical indices of obesity may be at increased risk of metabolic diseases despite their “normal” size. There is a need for accurate quantification of these potentially hazardous depots and identification of novel subphenotypes that recognize individuals at potentially increased metabolic risk. We aimed to calculate a reference range for total and regional adipose tissue (AT) as well as ectopic fat in liver and muscle in healthy subjects. We studied the relationship between age, body‐mass, BMI, waist circumference (WC), and the distribution of AT, using whole‐body magnetic resonance imaging (MRI), in 477 white volunteers (243 male, 234 female). Furthermore, we used proton magnetic resonance spectroscopy (MRS) to determine intrahepatocellular (IHCL) and intramyocellular (IMCL) lipid content. The anthropometric variable which provided the strongest individual correlation for adiposity and ectopic fat stores was WC in men and BMI in women. In addition, we reveal a large variation in IAAT, abdominal subcutaneous AT (ASAT), and IHCL depots not fully predicted by clinically obtained measurements of obesity and the emergence of a previously unidentified subphenotype. Here, we demonstrate gender‐ and age‐specific patterns of regional adiposity in a large UK‐based cohort and identify anthropometric variables that best predict individual adiposity and ectopic fat stores. From these data we propose the thin‐on‐the‐outside fat‐on‐the‐inside (TOFI) as a subphenotype for individuals at increased metabolic risk.

Preferential loss of visceral fat following aerobic exercise, measured by magnetic resonance imaging.

The aim of this study was to use whole-body magnetic resonance imaging (MRI) together with biochemical and anthropometric measurements to study the influence of regular moderate exercise with no dietary intervention on adipose tissue distribution in nonobese healthy women. We found significant decreases in both total (28.86±2.24 vs. 27.00±2.27 liters, P<0.05) and regional fat depots (visceral fat: 1.68±0.21 vs. 1.26±0.18 liters, P<0.01) using whole-body MRI despite no significant change in body weight, body mass index, or the waist-to-hip ratio. Interestingly, no changes in body fat content were found using anthropometry or impedance. There was a significant increase in high density lipoprotein cholesterol (1.58 ±0.06 vs. 1.66±0.08 mmol/L P<0.02) following exercise although there were no changes in other blood lipids such as triglycerides. In summary, moderate aerobic exercise over a period of 6 mon resulted in a preferential loss in visceral fat in nonobese healthy women, and this may help to explain some of the health benefits associated with regular and moderate physical activity.

Polycystic Ovary Syndrome with Hyperandrogenism Is Characterized by an Increased Risk of Hepatic Steatosis Compared to Nonhyperandrogenic PCOS Phenotypes and Healthy Controls, Independent of Obesity and Insulin Resistance

CONTEXT Nonalcoholic fatty liver disease may be evident in women with polycystic ovary syndrome (PCOS), both conditions being associated with obesity and insulin resistance. However, few studies have accounted for the high prevalence of obesity in PCOS. OBJECTIVE The aim of this study was to determine whether PCOS is independently associated with hepatic steatosis, compared with healthy controls of similar age and body mass index (BMI), and whether steatosis is associated with hyperandrogenemia. DESIGN AND SETTING We conducted a cross-sectional, case-control study at two tertiary referral centers. PATIENTS Twenty-nine women with PCOS diagnosed by the Rotterdam criteria [aged 28 yr; 95% confidence interval (CI), 26-31; BMI, 33 kg/m2; 95% CI, 31-36] and 22 healthy controls (aged 29 yr; 95% CI, 28-31; BMI, 30 kg/m2; 95% CI, 28-33) were studied. METHODS Proton-magnetic resonance spectroscopy quantified hepatic and skeletal muscle fat; whole body magnetic resonance imaging quantified internal, visceral, and sc adipose tissue volumes. Differences were assessed between PCOS and controls using t tests, and between hyperandrogenic (HA) PCOS, PCOS with normal androgens (NA), and controls using analysis of covariance. RESULTS After statistical adjustment for BMI, HA-PCOS had significantly higher liver fat vs. NA-PCOS (3.7%; 95% CI, 0.6-13.1) and vs. controls (2.1%; 95% CI, 0.3-6.6). Similarly, after adjustment for homeostasis model assessment for insulin resistance, internal and visceral adipose tissue volumes, liver fat remained significantly greater in HA-PCOS compared to NA-PCOS and controls. CONCLUSION These data suggest that HA-PCOS is associated with hepatic steatosis, independent of obesity and insulin resistance.

Intracellular and extracellular skeletal muscle triglyceride metabolism during alternating intensity exercise in humans

1 The main purpose of this study was to evaluate non‐invasively with magnetic resonance spectroscopy (1H‐MRS) changes in the concentrations of intracellular (IT) and extracellular (between muscle fibres) triglycerides (ET) in skeletal muscles of trained males (age range: 24–38 years) during two standard exercise protocols of alternating velocities. 2 Protocol 1 consisted of locomotion in a shuttle manner between two lines 30 m apart at four different velocities (1, 2, 3 and 4 m s−1) which were alternated every minute in a standard routine for 90 min, whereas Protocol 2 included locomotion between two lines 20 m apart at only three velocities (2, 2.7 and 4 m s−1) until volitional exhaustion. The heart rate during both protocols fluctuated between 140 and 200 beats min−1. 3 Using pre‐exercise muscle water to quantify individual total creatine (TCr) that was utilized as an internal standard and assuming that TCr does not change during exercise, subjects’ mean IT and ET concentrations in soleus (Sol) muscle before Protocol 1 (n= 8) were 45.8 ± 4.8 mmol (kg dry weight)−1 (mean ± s.e.m.) and 93.1 ± 14.1 mmol (kg dry weight)−1, respectively. After the exercise, the concentrations of IT and ET were not significantly different from the values at rest. Before Protocol 2 (n= 4), IT concentrations in Sol, gastrocnemius (Gast) and tibialis (Tib) muscles were 46.4 ± 13.6, 35.0 ± 12.1 and 23.1 ± 4.8 mmol (kg dry weight)−1, respectively, and were not affected by the exhaustive exercise. The ET concentrations in Sol, Gast and Tib were 136.4 ± 38.1, 175.3 ± 86.5 and 79.3 ± 20.0 mmol (kg dry weight)−1, respectively, and they did not change significantly after exhaustion. 4 The study showed that levels of IT and ET were not affected by alternating intensity exercise to fatigue. This suggests that IT and ET in human Sol, Gast and Tib muscles do not contribute significantly to the energy turnover during this type of exercise. Energy for this type of muscle contraction may arise primarily from muscle phosphocreatine (PCr) and glycogen breakdown, circulating glucose and fatty acids from triglycerides other than those encountered within and between muscle cells.

Whole Body Magnetic Resonance Imaging of Healthy Newborn Infants Demonstrates Increased Central Adiposity in Asian Indians

Abdominal adiposity and metabolic ill health in Asian Indians are a growing public health concern. Causal pathways are unknown. Preventive measures in adults have had limited success. The aim of this observational case-control study was to compare adipose tissue partitioning in 69 healthy full term Asian Indian and white European newborns born in Pune, India and London, UK, respectively. The main outcome measures were total and regional adipose tissue content measured by whole body magnetic resonance imaging. Although smaller in weight (95% CI for difference −0.757 to −0.385 kg, p < 0.001), head circumference (−2.15 to −0.9 cm, p < 0.001), and length (−2.9 to −1.1 cm p < 0.001), the Asian Indian neonates had significantly greater absolute adiposity in all three abdominal compartments, internal (visceral) (0.012–0.023 L, p < 0.001), deep s.c. (0.003–0.017 L, p = 0.006) and superficial s.c. (0.006–0.043 L, p = 0.011) and a significant reduction in nonabdominal superficial s.c. adipose tissue (−0.184 to −0.029 L, p = 0.008) in comparison to the white European babies despite similar whole body adipose tissue content (−0.175 to 0.034 L, p = 0.2). We conclude that differences in adipose tissue partitioning exist at birth. Investigative, screening, and preventive measures must involve maternal health, intrauterine life, and infancy.