The interest in brown adipose tissue (BAT) as a target to combat metabolic disease has recently been renewed with the discovery of functional BAT in humans. In rodents, BAT can be activated by bile acids, which activate type 2 iodothyronine deiodinase (D2) in BAT via the G-coupled protein receptor TGR5, resulting in increased oxygen consumption and energy expenditure. Here we examined the effects of oral supplementation of the bile acid chenodeoxycholic acid (CDCA) on human BAT activity. Treatment of 12 healthy female subjects with CDCA for 2 days resulted in increased BAT activity. Whole-body energy expenditure was also increased upon CDCA treatment. In vitro treatment of primary human brown adipocytes derived with CDCA or specific TGR5 agonists increased mitochondrial uncoupling and D2 expression, an effect that was absent in human primary white adipocytes. These findings identify bile acids as a target to activate BAT in humans.

Background Nicotinamide riboside (NR) is an NAD+ precursor that boosts cellular NAD+ concentrations. Preclinical studies have shown profound metabolic health effects after NR supplementation. Objectives We aimed to investigate the effects of 6 wk NR supplementation on insulin sensitivity, mitochondrial function, and other metabolic health parameters in overweight and obese volunteers. Methods A randomized, double-blinded, placebo-controlled, crossover intervention study was conducted in 13 healthy overweight or obese men and women. Participants received 6 wk NR (1000 mg/d) and placebo supplementation, followed by broad metabolic phenotyping, including hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy, muscle biopsies, and assessment of ex vivo mitochondrial function and in vivo energy metabolism. Results Markers of increased NAD+ synthesis—nicotinic acid adenine dinucleotide and methyl nicotinamide—were elevated in skeletal muscle after NR compared with placebo. NR increased body fat-free mass (62.65% ± 2.49% compared with 61.32% ± 2.58% in NR and placebo, respectively; change: 1.34% ± 0.50%, P = 0.02) and increased sleeping metabolic rate. Interestingly, acetylcarnitine concentrations in skeletal muscle were increased upon NR (4558 ± 749 compared with 3025 ± 316 pmol/mg dry weight in NR and placebo, respectively; change: 1533 ± 683 pmol/mg dry weight, P = 0.04) and the capacity to form acetylcarnitine upon exercise was higher in NR than in placebo (2.99 ± 0.30 compared with 2.40 ± 0.33 mmol/kg wet weight; change: 0.53 ± 0.21 mmol/kg wet weight, P = 0.01). However, no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism. Conclusions NR supplementation of 1000 mg/d for 6 wk in healthy overweight or obese men and women increased skeletal muscle NAD+ metabolites, affected skeletal muscle acetylcarnitine metabolism, and induced minor changes in body composition and sleeping metabolic rate. However, no other metabolic health effects were observed. This trial was registered at clinicaltrials.gov as NCT02835664

Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Hepatic saturated fatty acids (SFA) may be a marker of DNL and are suggested to be most detrimental in contributing to insulin resistance. Here, we show in a cross-sectional study design (ClinicalTrials.gov ID: NCT03211299) that we are able to distinguish the fractions of hepatic SFA, mono-and polyunsaturated fatty acids in healthy and metabolically compromised volunteers using proton magnetic resonance spectroscopy (1 H-MRS). DNL is positively associated with SFA fraction and is elevated in patients with non-alcoholic fatty liver and type 2 diabetes. Intriguingly, SFA fraction shows a strong, negative correlation with hepatic insulin sensitivity. Our results show that the hepatic lipid composition, as determined by our 1 H-MRS methodology, is a measure of DNL and suggest that specifically the SFA fraction may hamper hepatic insulin sensitivity.

Aims/hypothesis Time-restricted eating (TRE) is suggested to improve metabolic health by limiting food intake to a defined time window, thereby prolonging the overnight fast. This prolonged fast is expected to lead to a more pronounced depletion of hepatic glycogen stores overnight and might improve insulin sensitivity due to an increased need to replenish nutrient storage. Previous studies showed beneficial metabolic effects of 6–8 h TRE regimens in healthy, overweight adults under controlled conditions. However, the effects of TRE on glucose homeostasis in individuals with type 2 diabetes are unclear. Here, we extensively investigated the effects of TRE on hepatic glycogen levels and insulin sensitivity in individuals with type 2 diabetes. Methods Fourteen adults with type 2 diabetes (BMI 30.5±4.2 kg/m2, HbA1c 46.1±7.2 mmol/mol [6.4±0.7%]) participated in a 3 week TRE (daily food intake within 10 h) vs control (spreading food intake over ≥14 h) regimen in a randomised, crossover trial design. The study was performed at Maastricht University, the Netherlands. Eligibility criteria included diagnosis of type 2 diabetes, intermediate chronotype and absence of medical conditions that could interfere with the study execution and/or outcome. Randomisation was performed by a study-independent investigator, ensuring that an equal amount of participants started with TRE and CON. Due to the nature of the study, neither volunteers nor investigators were blinded to the study interventions. The quality of the data was checked without knowledge on intervention allocation. Hepatic glycogen levels were assessed with 13C-MRS and insulin sensitivity was assessed using a hyperinsulinaemic–euglycaemic two-step clamp. Furthermore, glucose homeostasis was assessed with 24 h continuous glucose monitoring devices. Secondary outcomes included 24 h energy expenditure and substrate oxidation, hepatic lipid content and skeletal muscle mitochondrial capacity. Results Results are depicted as mean ± SEM. Hepatic glycogen content was similar between TRE and control condition (0.15±0.01 vs 0.15±0.01 AU, p=0.88). M value was not significantly affected by TRE (19.6±1.8 vs 17.7±1.8 μmol kg−1 min−1 in TRE vs control, respectively, p=0.10). Hepatic and peripheral insulin sensitivity also remained unaffected by TRE (p=0.67 and p=0.25, respectively). Yet, insulin-induced non-oxidative glucose disposal was increased with TRE (non-oxidative glucose disposal 4.3±1.1 vs 1.5±1.7 μmol kg−1 min−1, p=0.04). TRE increased the time spent in the normoglycaemic range (15.1±0.8 vs 12.2±1.1 h per day, p=0.01), and decreased fasting glucose (7.6±0.4 vs 8.6±0.4 mmol/l, p=0.03) and 24 h glucose levels (6.8±0.2 vs 7.6±0.3 mmol/l, p<0.01). Energy expenditure over 24 h was unaffected; nevertheless, TRE decreased 24 h glucose oxidation (260.2±7.6 vs 277.8±10.7 g/day, p=0.04). No adverse events were reported that were related to the interventions. Conclusions/interpretation We show that a 10 h TRE regimen is a feasible, safe and effective means to improve 24 h glucose homeostasis in free-living adults with type 2 diabetes. However, these changes were not accompanied by changes in insulin sensitivity or hepatic glycogen. Trial registration ClinicalTrials.gov NCT03992248 Funding ZonMW, 459001013 Graphical abstract

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Mild cold acclimation for 10 days has been previously shown to markedly improve insulin sensitivity in patients with type 2 diabetes. Here we show in a single-arm intervention study (Trialregister.nl ID: NL4469/NTR5711) in nine patients with type 2 diabetes that ten days of mild cold acclimation (16–17 °C) in which observable, overt shivering was prevented, does not result in improved insulin sensitivity, postprandial glucose and lipid metabolism or intrahepatic lipid content and only results in mild effects on overnight fasted fat oxidation, postprandial energy expenditure and aortic augmentation index. The lack of marked metabolic effects in this study is associated with a lack of self-reported shivering and a lack of upregulation of gene expression of muscle activation or muscle contraction pathways in skeletal muscle and suggests that some form of muscle contraction is needed for beneficial effects of mild cold acclimation.

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Purpose of review Nonalcoholic fatty liver is the result of an imbalance between lipid storage [from meal, de novo lipogenesis (DNL) and fatty acid (FA) uptake] and disposal (oxidation and VLDL output). Knowledge on the contribution of each of these pathways to liver fat content in humans is essential to develop tailored strategies to prevent and treat nonalcoholic fatty liver. Here, we review the techniques available to study the different storage pathways and review dietary modulation of these pathways. Recent findings The type of carbohydrate and fat could be of importance in modulating DNL, as complex carbohydrates and omega-3 FAs have been shown to reduce DNL. No effects were found on the other pathways, however studies investigating this are scarce. Summary Techniques used to assess storage pathways are predominantly stable isotope techniques, which require specific expertise and are costly. Validated biomarkers are often lacking. These methodological limitations also translate into a limited number of studies investigating to what extent storage pathways can be modulated by diet. Further research is needed to elucidate in more detail the impact that fat and carbohydrate type can have on liver fat storage pathways and content.