Rab18 maintains homeostasis of subcutaneous adipose tissue to prevent obesity-induced metabolic disorders.

Metabolically healthy obesity refers to obese individuals who do not develop metabolic disorders. These people store fat in subcutaneous adipose tissue (SAT) rather than in visceral adipose tissue (VAT). However, the molecules participating in this specific scenario remain elusive. Rab18, a lipid droplet (LD)-associated protein, mediates the contact between the endoplasmic reticulum (ER) and LDs to facilitate LD growth and maturation. In the present study, we show that the protein level of Rab18 is specifically upregulated in the SAT of obese people and mice. Rab18 adipocyte-specific knockout (Rab18 AKO) mice had a decreased volume ratio of SAT to VAT compared with wildtype mice. When subjected to high-fat diet (HFD), Rab18 AKO mice had increased ER stress and inflammation, reduced adiponectin, and decreased triacylglycerol (TAG) accumulation in SAT. In contrast, TAG accumulation in VAT, brown adipose tissue (BAT) or liver of Rab18 AKO mice had a moderate increase without ER stress stimulation. Rab18 AKO mice developed insulin resistance and systematic inflammation. Rab18 AKO mice maintained body temperature in response to acute and chronic cold induction with a thermogenic SAT, similar to the counterpart mice. Furthermore, Rab18-deficient 3T3-L1 adipocytes were more prone to palmitate-induced ER stress, indicating the involvement of Rab18 in alleviating lipid toxicity. Rab18 AKO mice provide a good animal model to investigate metabolic disorders such as impaired SAT. In conclusion, our studies reveal that Rab18 is a key and specific regulator that maintains the proper functions of SAT by alleviating lipid-induced ER stress.

Metabolic switch from glycogen to lipid in the liver maintains glucose homeostasis in neonatal mice.

Neonates strive to acquire energy when the continuous transplacental nutrient supply ceases at birth, whereas milk consumption takes hours to start. Using murine models, we report the metabolic switches in the first days of life, with an unexpected discovery of glucose as the universal fuel essential for neonatal life. Blood glucose quickly drops as soon as birth, but immediately rebounds even before suckling and maintains stable afterward. Meanwhile, neonatal liver undergoes drastic metabolic changes, from extensive glycogenolysis before suckling to dramatically induced fatty acid oxidation (FAO) and gluconeogenesis after milk suckling. Unexpectedly, blocking hepatic glycogenolysis only caused a transient hypoglycemia before milk suckling without causing lethality. Limiting lipid supply in milk (low-fat milk, [LFM]) using Cidea-/- mice, however, led to a chronic and severe hypoglycemia and consequently claimed neonatal lives. While fat replenishment rescued LFM-caused neonatal lethality, the rescue effects were abolished by blocking FAO or gluconeogenesis, pointing to a funneling of lipids and downstream metabolites into glucose as the essential fuel. Finally, glucose administration also rescued LFM-caused neonatal lethality, independent on FAO or gluconeogenesis. Therefore, our results show that the liver works as an energy conversion center to maintain blood glucose homeostasis in neonates, providing theoretical basis for managing infant hypoglycemia.

Impact of Daily Consumption of Whole-Grain Quinoa-Enriched Bread on Gut Microbiome in Males.

Diets rich in whole grains are associated with improved health and a lower risk of non-communicable diseases, but the mechanisms through which these health benefits are conveyed are uncertain. One mechanism may be improvements in the gut environment by the delivery of fermentable substrates and associated phytochemicals to the lower gut and modification of the gut microbiome. Quinoa is included in the whole-grain category because of its structural similarities to cereals but the effects of its consumption on the gut microbiome have not been investigated to date. Our aim was to examine the impact of daily quinoa consumption on the gut microbiome in a 4-week randomised cross-over intervention separated by a 4-week wash-out period involving 28 adult males. Participants consumed either a quinoa-enriched wheat-bread roll providing 20 g quinoa flour each day, or a control wheat-only bread roll. Stool samples were collected in sterile collection tubes immediately before and at the end of each intervention period. DNA was then extracted, and the 16S rRNA V4 region of extracted DNA was amplified and sequenced. For both the control and quinoa bread periods, there were no changes at the phyla or genus level between baseline and week 4 (all p > 0.05). Diversity in the microbiome profile was not different from baseline after either intervention arms. The results show that small changes in the type of cereal consumed­substituting 20 g of refined wheat flour with whole-grain quinoa flour­was not able to significantly modulate the gut microbiome. Further studies with higher levels of quinoa or longer exposure periods are needed to ascertain if there is a dose−response effect of quinoa, and if these effects are able to translate into clinical outcomes.

Neonatal ketone body elevation regulates postnatal heart development by promoting cardiomyocyte mitochondrial maturation and metabolic reprogramming.

Neonatal heart undergoes metabolic conversion and cell cycle arrest preparing for the increased workload during adulthood. Herein, we report that neonatal ketone body elevation is a critical regulatory factor for postnatal heart development. Through multiomics screening, we found that the expression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the rate-limiting enzyme of ketogenesis, was transiently induced by colostrum in the neonatal heart. Hmgcs2 knockout caused mitochondrial maturation defects. Meanwhile, postnatal heart development was compromised and cardiomyocytes reacquired proliferation capacity in Hmgcs2 knockout mice. Consequently, over 40% of newborn Hmgcs2 knockout mice died before weaning. The heart function of surviving Hmgcs2 knockout mice was also impaired, which could be rescued by ketone body supplementation during the suckling stage. Mechanistically, ketone body deficiency inhibited ß-hydroxybutyrylation but enhanced acetylation of mitochondrial proteins, which might be responsible for the inhibition of the enzyme activity in mitochondria. These observations suggest that ketone body is critical for postnatal heart development through regulating mitochondrial maturation and metabolic reprogramming.

PITPNC1 promotes the thermogenesis of brown adipose tissue under acute cold exposure.

Brown adipose tissue (BAT) plays an essential role in non-shivering thermogenesis. The phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) is identified as a lipid transporter that reciprocally transfers phospholipids between intracellular membrane structures. However, the physiological significance of PITPNC1 and its regulatory mechanism remain unclear. Here, we demonstrate that PITPNC1 is a key player in thermogenesis of BAT. While Pitpnc1-/- mice do not differ with wildtype mice in body weight and insulin sensitivity on either chow or high-fat diet, they develop hypothermia when subjected to acute cold exposure at 4°C. The Pitpnc1-/- brown adipocytes exhibit defective ß-oxidation and abnormal thermogenesis-related metabolism pathways in mitochondria. The deficiency of lipid mobilization in Pitpnc1-/- brown adipocytes might be the result of excessive accumulation of phosphatidylcholine and a reduction of phosphatidic acid. Our findings have uncovered significant roles of PITPNC1 in mitochondrial phospholipid homeostasis and BAT thermogenesis.

Assessing the effects of inulin-type fructan intake on body weight, blood glucose, and lipid profile: A systematic review and meta-analysis of randomized controlled trials.

Inulin-type fructan (ITF) intake has been suggested to alleviate several features of metabolic syndrome including obesity, diabetes, and hyperlipidemia; yet, results from the human trials remained inconsistent. We aimed to systematically evaluate the effects of ITF intake on body weight, glucose homeostasis, and lipid profile on human subjects with different health status, including healthy, overweight and obese, prediabetes and diabetes, and hyperlipidemia. Weighted mean differences (WMDs) between ITF and control groups were calculated by a random-effects model. A total of 33 randomized controlled human trials were included. Significant effect of ITF intake was only observed in the diabetics, but not in the other subject groups. Specifically, ITF intervention significantly decreased the WMD of blood glucose (-0.42 mmol/L; 95% CI: -0.71, -0.14; p = .004), total cholesterol (-0.46 mmol/L; 95% CI: -0.75, -0.17; p = .002), and triglycerides (TAG) (-0.21 mmol/L; 95% CI: -0.37, -0.05; p = .01) compared with the control. The stability of these favorable effects of ITF on diabetics was confirmed by sensitivity analysis. Also, ITF tends to lower LDL cholesterol (p = .084). But body weight and blood insulin were not affected by ITF intake. It should be noted that blood glucose, total cholesterol, and LDL cholesterol exhibited high unexplained heterogeneity. In conclusion, ITF intake lowers blood glucose, total cholesterol, and TAG in the people with diabetes, and they may benefit from addition of inulin into their diets, but the underlying mechanisms responsible for these effects are inconclusive.

Chain length-dependent inulin alleviates diet-induced obesity and metabolic disorders in mice.

Dietary fiber is regarded to improve host metabolic disorders through modulating gut microbiota. The study was to investigate the effects of inulin with different degree of polymerization (DP) on adiposity, related metabolic syndrome, and the possible mechanisms from the points of gut microbiota and metabolite changes. C57Bl/6J male mice were randomly allocated to normal diet (ND) group, high-fat diet (HFD) group, two HFD groups with short-chain inulin (HFD-S) and medium and long-chain inulin (HFD-ML) for 8 weeks. Compared with HFD treatment, ML-inulin supplementation significantly decreased weight gain, hepatic steatosis, chronic inflammation, and increased insulin sensitivity, energy expenditure and thermogenesis. This could be mimicked by S-inulin supplementation to some degree although it is not as effective as ML inulin. Also, mice treated with S and ML inulin had a remarkable alternation in the composition of gut microbiota and increased the production of short-chain fatty acids (SCFAs). However, reduced serum levels of essential fatty acids, vitamins B1 and B3 by HFD were further decreased by both inulin supplementations. ML inulin can prevent HFD-induced obesity and the associated metabolic disorders, and may be used as novel gut microbiota modulator to prevent HFD-induced gut dysbiosis and metabolic disorders.

Cobalt-Catalyzed Three-Component Difluoroalkylation-Peroxidation of Alkenes.

The Co(acac)2-catalyzed three-component difluoroalkylation-peroxidation of alkenes with difluorohaloactates and hydroperoxides has been developed. The protocol provides an efficient and selective access to various ß-peroxyl difluoroalkyl derivatives, which can be transformed into α-amino acid and pyrimidine derivatives by the reactions with amines and amidines. The mild reaction conditions, broad substrate scopes, gram-scale synthesis, and synthetic applications exemplified the utility and practicability of this method. In addition, this methodology can be extended to other halide compounds to give the alkylation-peroxidation products.

Nitration-Peroxidation of Alkenes: A Selective Approach to ß-Peroxyl Nitroalkanes.

Nitration-peroxidation of alkenes for the synthesis of ß-peroxyl nitroalkanes has been developed by using tert-butyl nitrite and tert-butyl hydroperoxide. The method presents a new and selective difunctionalization of alkenes to introduce a nitro group and a peroxyl group across the double bonds of alkenes under mild conditions. A radical reaction pathway is proposed by experimental and theoretical studies.

Effects of Quinoa (Chenopodium quinoa Willd.) Consumption on Markers of CVD Risk.

A number of epidemiological studies have suggested that diets rich in whole grains are linked to lower cardiovascular disease (CVD) risk and mortality. Quinoa, a pseudo-cereal, is included in the “whole grain” category but the effects of quinoa consumption in humans is not widely studied. Our aim was to undertake a dietary intervention study to investigate the effects of daily consumption of quinoa-enriched bread (providing 20 g quinoa flour) on CVD risk markers compared with a 100% refined wheat bread control. Thirty-seven healthy overweight men (35⁻70 years, body mass index >25 kg/m²) completed a 4-week cross-over intervention, separated by a 4-week washout period. Fasting blood samples were collected at the beginning and end of each intervention period. Continuous glucose monitoring was undertaken at the end of each intervention period. After 4 weeks of intervention, blood glucose and low density lipoprotein (LDL) cholesterol were significantly lower than baseline in both groups but there was no difference between quinoa and control. Anthropometric measures and other blood metabolites were not different between the two treatments. The cumulative area under the blood glucose curve for the last 4 days of the quinoa intervention tended to be lower than the first 4 days of wash-out (p = 0.054), and was significantly lower than the corresponding period of the wheat treatment (p = 0.039). In conclusion, daily consumption of quinoa in this short-term intervention appears to modify glucose response, but has minimal effects on other CVD risk biomarkers.

Buckwheat and CVD Risk Markers: A Systematic Review and Meta-Analysis.

The effects of buckwheat intake on cardiovascular diseases (CVDs) have not been systematically investigated. The aim of the present study was to comprehensively summarize studies in humans and animals, evaluating the impact of buckwheat consumption on CVD risk markers and to conduct a meta-analysis of relevant data. Thirteen randomized, controlled human studies, two cross-sectional human studies and twenty-one animal studies were identified. Using random-effects models, the weighted mean difference of post-intervention concentrations of blood glucose, total cholesterol and triglycerides were significantly decreased following buckwheat intervention compared with controls [differences in blood glucose: -0.85 mmol/L (95% CI: -1.31, -0.39), total cholesterol: 0.50 mmol/L (95% CI: -0.80, -0.20) and triglycerides: 0.25 mmol/L (95% CI: -0.49, -0.02)]. Responses of a similar magnitude were seen in two cross-sectional studies. For animal studies, nineteen of twenty-one studies showed a significant reduction in total cholesterol of between 12% and 54%, and fourteen of twenty studies showed a significant reduction in triglycerides of between 2% and 74%. All exhibited high unexplained heterogeneity. There was inconsistency in HDL cholesterol outcomes in both human and animal studies. It remains unclear whether increased buckwheat intake significantly benefits other markers of CVD risk, such as weight, blood pressure, insulin, and LDL-cholesterol, and underlying mechanisms responsible for any effects are unclear.