Emanuel E. Canfora

Short-chain fatty acids in control of body weight and insulin sensitivity.

The connection between the gut microbiota and the aetiology of obesity and cardiometabolic disorders is increasingly being recognized by clinicians. Our gut microbiota might affect the cardiometabolic phenotype by fermenting indigestible dietary components and thereby producing short-chain fatty acids (SCFA). These SCFA are not only of importance in gut health and as signalling molecules, but might also enter the systemic circulation and directly affect metabolism or the function of peripheral tissues. In this Review, we discuss the effects of three SCFA (acetate, propionate and butyrate) on energy homeostasis and metabolism, as well as how these SCFA can beneficially modulate adipose tissue, skeletal muscle and liver tissue function. As a result, these SCFA contribute to improved glucose homeostasis and insulin sensitivity. Furthermore, we also summarize the increasing evidence for a potential role of SCFA as metabolic targets to prevent and counteract obesity and its associated disorders in glucose metabolism and insulin resistance. However, most data are derived from animal and in vitro studies, and consequently the importance of SCFA and differential SCFA availability in human energy and substrate metabolism remains to be fully established. Well-controlled human intervention studies investigating the role of SCFA on cardiometabolic health are, therefore, eagerly awaited.

Colonic infusions of short-chain fatty acid mixtures promote energy metabolism in overweight/obese men : a randomized crossover trial

Short-chain fatty acids (SCFA), formed by microbial fermentation, are believed to be involved in the aetiology of obesity and diabetes. This study investigated the effects of colonic administration of physiologically relevant SCFA mixtures on human substrate and energy metabolism. In this randomized, double-blind, crossover study, twelve normoglycaemic men (BMI 25–35 kg/m2) underwent four investigational days, during which SCFA mixtures (200 mmol/L) high in either acetate (HA), propionate (HP), butyrate (HB) or placebo (PLA) were rectally administered during fasting and postprandial conditions (oral glucose load). Before and for two hours after colonic infusions, indirect calorimetry was performed and blood samples were collected. All three SCFA mixtures increased fasting fat oxidation (P < 0.01), whilst resting energy expenditure increased after HA and HP compared with PLA (P < 0.05). In addition, all three SCFA mixtures increased fasting and postprandial plasma peptide YY (PYY) concentrations, and attenuated fasting free glycerol concentrations versus PLA (P < 0.05). Colonic infusions of SCFA mixtures, in concentrations and ratios reached after fibre intake, increased fat oxidation, energy expenditure and PYY, and decreased lipolysis in overweight/obese men. Human intervention studies are warranted to investigate whether these effects translate into long-term benefits for body weight control and insulin sensitivity in the obese insulin resistant state.

The role of polydextrose in body weight control and glucose regulation.

Purpose of reviewThe purpose of this review was to highlight recent research developments on effects of the dietary fibre polydextrose (PDX) on appetite, satiety and energy intake and glucose metabolism. For this purpose, clinically relevant human studies were reviewed and putative mechanisms and pathways were discussed. Recent findingsA number of acute human intervention studies provide strong indications for an energy and glucose metabolism-regulating role of PDX. These effects might be mediated via a reduced gastro-intestinal transit reducing glycaemia and insulinemia after PDX ingestion and the potential of PDX as soluble dietary fibre to alter the intestinal microbial composition, which might lead to changes in signalling in both peripheral and central pathways involved in energy metabolism and glucose homeostasis. SummaryIn acute studies, PDX seems to have an inhibiting effect on energy intake and satiety and to reduce glycaemic and insulinemic response through effect on gastro-intestinal transit time and macronutrient absorption as well as through effects of the microbial products such as short-chain fatty acids on energy and substrate metabolism. In particular, well controlled human intervention studies are required to confirm these effects in the long term. Overall, supplement PDX to the daily diet may be a promising approach for the management and treatment of obesity and associated metabolic disorders.

Gut microbiota composition strongly correlates to peripheral insulin sensitivity in obese men but not in women

Gut microbiota composition may play an important role in the development of obesity-related comorbidities. However, only few studies have investigated gender-differences in microbiota composition and gender-specific associations between microbiota or microbial products and insulin sensitivity. Insulin sensitivity (hyperinsulinemic-euglycemic clamp), body composition (dual energy X-ray absorptiometry), substrate oxidation (indirect calorimetry), systemic inflammatory markers and microbiota composition (PCR) were determined in male (n=15) and female (n=14) overweight and obese subjects. Bacteroidetes/Firmicutes-ratio was higher in men than in women (P=0.001). Bacteroidetes/Firmicutes-ratio was inversely related to peripheral insulin sensitivity only in men (men: P=0.003, women: P=0.882). This association between Bacteroidetes/Firmicutes-ratio and peripheral insulin sensitivity did not change after adjustment for dietary fibre and saturated fat intake, body composition, fat oxidation and markers of inflammation. Bacteroidetes/Firmicutes-ratio was not associated with hepatic insulin sensitivity. Men and women differ in microbiota composition and its impact on insulin sensitivity, implying that women might be less sensitive to gut microbiota-induced metabolic aberrations than men. This trial was registered at clinicaltrials.gov as NCT02381145.

Acetate : a diet-derived key metabolite in energy metabolism: good or bad in context of obesity and glucose homeostasis?

Purpose of review To highlight recent research findings on effects of the short-chain fatty acid acetate in the control of body weight, insulin sensitivity, and glucose homeostasis. For this purpose, relevant animal and human in-vivo studies were reviewed and putative mechanisms and pathways were discussed. Recent findings Animal and human in-vivo studies provide strong indications for a beneficial role of orally ingested or colonically derived acetate, in the energy and substrate metabolism, thereby preventing or reversing the obese insulin-resistant phenotype. However, data from rodents are conflicting and indicate that an increased acetate turnover promotes body weight gain and insulin resistance. A reason for these controversies may be related to the mode and site of acetate administration, as well as to the species and the metabolic phenotype of animals used. Summary Overall, animal and human data suggest a direct regulatory role of acetate in several pathways involved in energy expenditure and fat utilization. In addition, acetate stimulates the release of gut-derived satiety-stimulating hormones and might regulate the inflammatory state. However, human intervention studies are required to evaluate the recent ‘acetate discrepancies’ and to confirm whether an increase in the acetate availability is a promising approach for the prevention and management of obesity and associated impairments in glucose and insulin metabolism.

Short-Chain Fatty Acids Differentially Affect Intracellular Lipolysis in a Human White Adipocyte Model

Background and aims Gut-derived short-chain fatty acids (SCFA), formed by microbial fermentation of dietary fibers, are believed to be involved in the etiology of obesity and diabetes. Previous data from our group showed that colonic infusions of physiologically relevant SCFA mixtures attenuated whole-body lipolysis in overweight men. To further study potential mechanisms involved in the antilipolytic properties of SCFA, we aimed to investigate the in vitro effects of SCFA incubations on intracellular lipolysis and signaling using a human white adipocyte model, the human multipotent adipose tissue-derived stem (hMADS) cells. Methods hMADS adipocytes were incubated with mixtures of acetate, propionate, and butyrate or single SCFA (acetate, propionate and butyrate) in concentrations ranging between 1 µmol/L and 1 mmol/L. Glycerol release and lipase activation was investigated during basal conditions and following β-adrenergic stimulation. Results SCFA mixtures high in acetate and propionate decreased basal glycerol release, when compared to control (P < 0.05), while mixtures high in butyrate had no effect. Also, β-adrenergic receptor mediated glycerol release was not significantly altered following incubation with SCFA mixtures. Incubation with only acetate decreased basal (1 µmol/L) and β-adrenergically (1 µmol/L and 1 mmol/L) mediated glycerol release when compared with control (P < 0.05). In contrast, butyrate (1 µmol/L) slightly increased basal and β-adrenergically mediated glycerol release compared with control (P < 0.05), while propionate had no effect on lipolysis. The antilipolytic effect of acetate was accompanied by a reduced phosphorylation of hormone-sensitive lipase (HSL) at serine residue 650. In addition, inhibition of Gi G proteins following pertussis toxin treatment prevented the antilipolytic effect of acetate. Conclusion The present data demonstrated that acetate was mainly responsible for the antilipolytic effects of SCFA and acts via attenuation of HSL phosphorylation in a Gi-coupled manner in hMADS adipocytes. Therefore, the modulation of colonic and circulating acetate may be an important target to modulate human adipose tissue lipid metabolism.

Gastrointestinal Transit Time, Glucose Homeostasis and Metabolic Health: Modulation by Dietary Fibers

Gastrointestinal transit time may be an important determinant of glucose homeostasis and metabolic health through effects on nutrient absorption and microbial composition, among other mechanisms. Modulation of gastrointestinal transit may be one of the mechanisms underlying the beneficial health effects of dietary fibers. These effects include improved glucose homeostasis and a reduced risk of developing metabolic diseases such as obesity and type 2 diabetes mellitus. In this review, we first discuss the regulation of gastric emptying rate, small intestinal transit and colonic transit as well as their relation to glucose homeostasis and metabolic health. Subsequently, we briefly address the reported health effects of different dietary fibers and discuss to what extent the fiber-induced health benefits may be mediated through modulation of gastrointestinal transit.

The prebiotic inulin improves substrate metabolism and promotes short-chain fatty acid production in overweight to obese men

BACKGROUND AND AIMS Human gut microbiota play an important role in maintaining human health. Dietary fibers, i.e. prebiotics, are fermented by human gut microbiota into the short-chain fatty acids (SCFAs) acetate, propionate, and butyrate. SCFAs promote fat oxidation and improve metabolic health. Therefore, the prebiotic inulin might be an effective dietary strategy to improve human metabolism. We aimed to investigate the acute metabolic effects of ingesting inulin compared with digestible carbohydrates and to trace inulin-derived SCFAs using stable isotope tracer methodology. METHODS In a double-blind, randomized, placebo-controlled crossover design, 14 healthy, overweight to obese men consumed a high-fat milkshake containing A) 24 g inulin of which 0.5 g was U-13C-inulin (INU) or B) 24 g maltodextrin placebo (PLA), with a wash-out period of at least five days. Fat oxidation was measured via an open-circuit ventilated hood and blood samples were collected up to 7 h after ingestion. Plasma, breath, and fecal samples were collected, and appetite and satiety scores were assessed. RESULTS Fat oxidation increased in the early postprandial phase (0-3 h), and both plasma glucose and insulin were lower after INU ingestion compared with PLA (all P < 0.05). Plasma free fatty acids were higher in the early, and lower in the late postprandial period after INU ingestion. Inulin was fermented into SCFAs as indicated by higher plasma acetate concentrations after INU compared with PLA (P < 0.05). In addition, we found continuous increases in plasma 13C-SCFA enrichments (P < 0.05 from t = 120 onwards) and breath 13CO2 enrichments after INU intake. There were no effects on plasma triglycerides, free glycerol, satiety hormones GLP-1 and PYY, and appetite and satiety scores. CONCLUSIONS Ingestion of the prebiotic inulin improves fat oxidation and promotes SCFA production in overweight to obese men. Overall, replacing digestible carbohydrates with the fermentable inulin may favor human substrate metabolism. CLINICAL TRIAL REGISTRY The trial was registered at clinicaltrials.gov under number NCT02009670.

Effects of gut microbiota manipulation on ex vivo lipolysis in human abdominal subcutaneous adipocytes

ABSTRACT The intestinal microbiota may contribute to the development of obesity by affecting host lipid metabolism and insulin sensitivity. To investigate the effects of microbiota manipulation on ex vivo basal and β-adrenergically-stimulated lipolysis in human adipocytes, 36 obese men were randomized to amoxicillin (broad-spectrum antibiotic), vancomycin (narrow-spectrum antibiotic) or placebo treatment (7 d, 1500 mg/d). Before and after treatment, ex vivo adipose tissue lipolysis was assessed under basal conditions and during stimulation with the non-selective β-agonist isoprenaline using freshly isolated mature adipocytes. Gene (targeted microarray) and protein expression were analyzed to investigate underlying pathways. Antibiotics treatment did not significantly affect basal and maximal isoprenaline-mediated glycerol release from adipocytes. Adipose tissue β-adrenoceptor expression or post-receptor signalling was also not different between groups. In conclusion, 7 d oral antibiotics treatment has no effect on ex vivo lipolysis in mature adipocytes derived from adipose tissue of obese insulin resistant men.