Small molecule inhibition of with no lysine kinase 1 (WNK1) (WNK463) signaling activates adenosine monophosphate-activated protein kinase signaling and mitigates membrane enrichment of glucose transporters 1 and 4, which decreases protein O-GlcNAcylation and glycation. Quantitative proteomics of right ventricular (RV) mitochondrial enrichments shows WNK463 prevents down-regulation of several mitochondrial metabolic enzymes. and metabolomics analysis suggests multiple metabolic processes are corrected. Physiologically, WNK463 augments RV systolic and diastolic function independent of pulmonary arterial hypertension severity. Hypochloremia, a condition of predicted WNK1 activation in patients with pulmonary arterial hypertension, is associated with more severe RV dysfunction. These results suggest WNK1 may be a druggable target to combat metabolic dysregulation and may improve RV function and survival in pulmonary arterial hypertension.

UNASSIGNED: Panax ginseng Meyer has been used as a nourishing edible herb in East Asia for thousands of years. 25-OH-PPT was first discovered as a natural rare triterpenoid saponin in ginseng stems and leaves by our group. Research found that it showed strong inhibitory effects on α-glucosidase and protein tyrosine phosphatase 1B, and protected cardiocytes (H9c2) through PI3K/Akt pathway.
UNASSIGNED: In the research, in order to optimize the 25-OH-PPT enrichment process, optimal macroporous resins and optimal purification conditions were studied. Meanwhile, the hypoglycemic effect and mechanism of 25-OH-PPT were evaluated by using STZ to establish insulin-dependent diabetic mice and the spontaneous type 2 diabetes DB/DB mice.
UNASSIGNED: Research found that 25-OH-PPT can reduce blood glucose and enhance glucose tolerance in STZ model mice. It increases insulin sensitivity by upregulating GLUT4 and AMPK in skeletal muscle, and activating insulin signaling pathways. In DB/DB mice, 25-OH-PPT achieves hypoglycemic effects mainly by activating the insulin signaling pathway. Meanwhile, through the influence of liver inflammatory factors and lipids in serum, it can be seen that 25-OH-PPT has obvious anti-inflammatory and lipid-lowering effects. These results provide new insights into the study of ginseng as a functional food.

This essay aims to make investigation on the mechanism of glucose metabolism disorder and Lipopolysaccharide administration-induced cognitive function impairment in adult rats with surgery.
METHODS: Divide the objects, 40 male Sprague-Dawley rats at the age of 9 months, into 4 groups. Provide unilateral nephrectomy surgery and/or lipopolysaccharide intraperitoneal injection. Postoperative cognitive function evaluation would be tested by the Morris water maze. Rats with Postoperative Cognitive Dysfunction (POCD) were scanned to analyze the brain glucose metabolism by means of 18F-FDG PET/CT. Phosphatidylinositol 3-Kinase (PI3K), Protein Kinase β (AKT), Insulin Substrates Receptor-2 (IRS-2) and Glucose Transporter 4 (GLUT4) were detected as well. Data will be captured through gene expression in POCD rats via Quantitative Real-Time PCR (QRT-PCR). On the other side, Western Blot was used to measure the expression levels of IRS-2, p-IRS-2, p-PI3K, PI3K, p-AKT, AKT, GLUT4, and p-GLUT4.
RESULTS: During the Morris water maze test, the staging time (latency) of rats in each group was becoming short gradually as the training progressed. The incubation time of Day 5 of each group was shorter than that of Day 1 (P < 0.05). On the Day 3 after the surgery, the average target quadrant residence time of Group S+L (100 μg/Kg) was shorter, compared with Group C, L and S. Of which, the average number of perforation was reduced greater than that of Group C (P < 0.05). The average swimming speed of the groups is of no distinct difference (P > 0.05). After the operation, there was no great difference shown among the subjects (P > 0.05) in the average residence time of the target quadrant, the mean number of passages, and the mean swimming speed. On Day 3, the average latency of Group S+L (100 μg/Kg) was longer than Group C (P < 0.05) in the working memory test after the operation. The average latency of rats in Group L and S was showed longer than that in Group C, with tiny difference (P > 0.05). In the 7-Day working memory test, the average latency of the rats in Group L, S and S+L (100 μg/Kg) was obviously longer than that in Group C. Comparing to preoperative rats, POCD rats of Group S+L (100 μg/Kg) were scanned by 18F-FDG PET/CT three days later after the operation. Its SUVmax of the frontal and temporal lobe areas were decreased significantly (P < 0.05). However, difference degree was not significantly shown in the SUVmax between Group C and the preoperative rats (P > 0.05). In comparison with the gene expression of of Group C, the PI3K, IRS-2, AKT and GLUT4 mRNA genes are the key genes in the insulin signaling pathways of the hippocampus of the POCD rats. The expression level was reduced. The expression level of all protein of PI3K, IRS-2, GLUT4 and AKT in the POCD rats was of no great contrast with that in Group C. But for IRS-2 protein, the phosphorylation level has increased, and meanwhile decreased for AKT, PI3K and GLUT4 proteins (P < 0.05).
CONCLUSIONS: Adult SD rats cognitive dysfunction model treated with unilateral nephrectomy combined and 100 μg/kg LPS intraperitoneal injection were led to abnormal both brain glucose metabolism and insulin expression. The proved phenomenal results signal pathway-related proteins PI3K, IRS-2, AKT and GLUT4. It reached the conclusion that surgical trauma, rather than anesthesia, leads to impaired cognitive function. PI3K, IRS-2, AKT, and GLUT4pathway of brain can be partial explanations of the pathogenesis of POCD.

The aim of this study was to investigate the associations of accelerometer-assessed sedentary time and breaks in sedentary time with 24-h events and duration of hypoglycaemia (<3.9 mmol/l), euglycaemia (3.9-7.8 mmol/l), hyperglycaemia (>7.8 mmol/l) and above target glucose (>9 mmol/l). Thirty-seven participants with type 2 diabetes (age, 62.8 ± 10.5 years; body mass index, 29.6 ± 6.8 kg/m2) in Glasgow, United Kingdom were enrolled between February 2016 and February 2017. Participants wore an activity monitor (activPAL3) recording the time and pattern of sedentary behaviour and a continuous glucose monitoring (CGM, Abbott FreeStyle Libre) for up to 14 days. Linear regression analyses were used to investigate the associations. Participants spent 3.7%, 64.7%, 32.1% and 19.2% of recording h/day in hypoglycaemia, euglycaemia, hyperglycaemia and above target, respectively. There was a negative association between sedentary time and time in euglycaemia (β = -0.44, 95% CI -0.86; -0.03, p = 0.04). There was a trend towards a positive association between sedentary time and time in hyperglycaemia (β = 0.36, 95% CI -0.05; 0.78, p = 0.08). Breaks in sedentary time was associated with higher time in euglycaemia (β = 0.38, 95% CI 0.00; 0.75, p = 0.04). To conclude, in individuals with type 2 diabetes, more time spent in unbroken and continuous sedentary behaviour was associated with poorer glucose control. Conversely, interrupting sedentary time with frequent breaks appears to improve glycaemic control. Therefore, this should be considered as a simple adjunct therapy to improve clinical outcomes in type 2 diabetes.

In patients with sepsis, liver metabolism and its capacity to provide other organs with energetic substrates are impaired. This and many other pathophysiological changes seen in human patients are reproduced in mice injected with purified endotoxin (lipopolysaccharide, LPS). In the present study, down-regulation of genes involved in hepatic fatty acid oxidation (FAOx) and gluconeogenesis in mice exposed to LPS was challenged by nutritional intervention with Argan oil. Mice given a standard chow supplemented or not with either 6% (w/w) Argan oil (AO) or 6% (w/w) olive oil (OO) prior to exposure to LPS were explored for liver gene expressions assessed by mRNA transcript levels and/or enzyme activities. AO (or OO) food supplementation reveals that, in LPS-treated mice, hepatic expression of genes involved in FAOx and gluconeogenesis was preserved. This preventive protection might be related to the recovery of the gene expressions of nuclear receptors peroxisome proliferator-activated receptor α (PPARα) and estrogen related receptor α (ERRα) and their coactivator peroxisome proliferator-activated receptor gamma coactivator-1α, (PGC-1α). These preventive mechanisms conveyed by AO against LPS-induced metabolic dysregulation might add new therapeutic potentialities in the management of human sepsis.

Fibroblast-growth factor 21 (FGF21) is thought to be important in metabolic regulation. Recently, low protein diets have been shown to increase circulating FGF21 levels. However, when energy contribution from dietary protein is lowered, other macronutrients, such as carbohydrates, must be increased to meet eucaloric balance. This raises the possibility that intake of a diet rich in carbohydrates may induce an increase in plasma FGF21 levels per se. Here we studied the role of dietary carbohydrates on the levels of circulating FGF21 and concomitant physiologic effects by feeding healthy men a carbohydrate rich diet without reducing protein intake.
A diet enriched in carbohydrates (80 E% carbohydrate; CHO) and a eucaloric control diet (CON) were provided to nine healthy men for three days. The energy intake during the CHO diet was increased (+75% energy) to ensure similar dietary protein intake in CHO and CON. To control for the effect of caloric surplus, we similarly overfed (+75% energy) the same subjects for three days with a fat-rich diet (78 E% fat; FAT), consisting of primarily unsaturated fatty acids. The three diets were provided in random order.
After CHO, plasma FGF21 concentration increased 8-fold compared to CON (329 ± 99 vs. 39 ± 9 pg ml-1, p < 0.05). In contrast, after FAT only a non-significant tendency (p = 0.073) to an increase in plasma FGF21 concentration was found. The increase in FGF21 concentration after CHO correlated closely (r = 0.88, p < 0.01) with increased leg glucose uptake (62%, p < 0.05) and increased hepatic glucose production (17%, p < 0.01), indicating increased glucose turnover. Plasma fatty acid (FA) concentration was decreased by 68% (p < 0.01), supported by reduced subcutaneous adipose tissue HSL Ser660 phosphorylation (p < 0.01) and perilipin 1 protein content (p < 0.01), pointing to a suppression of adipose tissue lipolysis. Concomitantly, a 146% increase in the plasma marker of hepatic de novo lipogenesis C16:1 n-7 FA (p < 0.01) was observed together with 101% increased plasma TG concentration (p < 0.001) in association with CHO intake and increased plasma FGF21 concentration.
Excess dietary carbohydrate, but not fat, led to markedly increased FGF21 secretion in humans, notably without protein restriction, and affected glucose and lipid homeostais.

Obesity is an increasingly prevalent and preventable morbidity with multiple behavioral, surgical and pharmacological interventions currently available. Commercial dietary supplements are often advertised to stimulate metabolism and cause rapid weight and/or fat loss, although few well-controlled studies have demonstrated such effects. We describe a commercially available dietary supplement (purportedly containing caffeine, catechins, and other metabolic stimulators) on resting metabolic rate in humans, and on metabolism, mitochondrial content, and related gene expression in vitro. Human males ingested either a placebo or commercially available supplement (RF) in a randomized double-blind placebo-controlled cross-over fashion. Metabolic rate, respiratory exchange ratio, and blood pressure were measured hourly for 3 h post-ingestion. To investigate molecular effects, human rhabdomyosarcoma cells (RD) and mouse myocytes (C2C12) were treated with various doses of RF for various durations. RF enhanced energy expenditure and systolic blood pressure in human males without altering substrate utilization. In myocytes, RF enhanced metabolism, metabolic gene expression, and mitochondrial content suggesting RF may target common energetic pathways which control mitochondrial biogenesis. RF appears to increase metabolism immediately following ingestion, although it is unclear if RF provides benefits beyond those provided by caffeine alone. Additional research is needed to examine safety and efficacy for human weight loss.

OBJECTIVE: Skeletal muscle AMP-activated protein kinase (AMPK) is important for regulating glucose homeostasis, mitochondrial content and exercise capacity. R419 is a mitochondrial complex-I inhibitor that has recently been shown to acutely activate AMPK in myotubes. Our main objective was to examine whether R419 treatment improves insulin sensitivity and exercise capacity in obese insulin resistant mice and whether skeletal muscle AMPK was important for mediating potential effects.
METHODS: Glucose homeostasis, insulin sensitivity, exercise capacity, and electron transport chain content/activity were examined in wildtype (WT) and AMPK β1β2 muscle-specific null (AMPK-MKO) mice fed a high-fat diet (HFD) with or without R419 supplementation.
RESULTS: There was no change in weight gain, adiposity, glucose tolerance or insulin sensitivity between HFD-fed WT and AMPK-MKO mice. In both HFD-fed WT and AMPK-MKO mice, R419 enhanced insulin tolerance, insulin-stimulated glucose disposal, skeletal muscle 2-deoxyglucose uptake, Akt phosphorylation and glucose transporter 4 (GLUT4) content independently of alterations in body mass. In WT, but not AMPK-MKO mice, R419 improved treadmill running capacity. Treatment with R419 increased muscle electron transport chain content and activity in WT mice; effects which were blunted in AMPK-MKO mice.
CONCLUSIONS: Treatment of obese mice with R419 improved skeletal muscle insulin sensitivity through a mechanism that is independent of skeletal muscle AMPK. R419 also increases exercise capacity and improves mitochondrial function in obese WT mice; effects that are diminished in the absence of skeletal muscle AMPK. These findings suggest that R419 may be a promising therapy for improving whole-body glucose homeostasis and exercise capacity.

Adipose tissue remodeling occurs in obesity, characterized by adipocyte hypertrophy and increased infiltration of macrophages which also shift to a proinflammatory phenotype. Factors derived from these macrophages significantly alter adipocyte function, such as repressing adipogenesis, inducing inflammatory response and desensitizing insulin action. As macrophages produce a cocktail of inflammatory signals, identifying the key factors that mediate the detrimental effects may offer effective therapeutic targets. IL-1β, a major cytokine produced largely by macrophages, is implicated in the development of obesity-associated insulin resistance. In this article, we discuss recent advances in our understanding of the role of IL-1β in macrophage-adipocyte crosstalk in obesity. IL-1β impairs insulin sensitivity in adipose tissue by inhibition of insulin signal transduction. Blocking the activity of IL-1β, its receptor binding or production improves insulin signaling and action in human adipocytes. This is in parallel with a reduction in macrophage-stimulated proinflammatory profile and lipolysis. Targeting IL-1β may be beneficial for protecting against obesity-related insulin resistance at the tissue and systemic levels.

Growth hormone (GH) supplementation therapy to adults with GH deficiency has beneficial effects on adipose tissue lipid metabolism, improving thus adipocyte functional morphology and insulin sensitivity. However, molecular nature of these effects remains unclear. We therefore tested the hypothesis that lipid-mobilizing adipokine zinc-α2-glycoprotein is causally linked to GH effects on adipose tissue lipid metabolism. Seventeen patients with severe GH deficiency examined before and after the 5-year GH replacement therapy were compared with age-, gender- and BMI-matched healthy controls. Euglycemic hyperinsulinemic clamp was used to assess whole-body and adipose tissue-specific insulin sensitivity. Glucose tolerance was determined by oGTT, visceral and subcutaneous abdominal adiposity by MRI, adipocyte size morphometrically after collagenase digestion, lipid accumulation and release was studied in differentiated human primary adipocytes in association with GH treatment and zinc-α2-glycoprotein gene silencing. Five-year GH replacement therapy improved glucose tolerance, adipose tissue insulin sensitivity and reduced adipocyte size without affecting adiposity and whole-body insulin sensitivity. Adipose tissue zinc-α2-glycoprotein expression was positively associated with whole-body and adipose tissue insulin sensitivity and negatively with adipocyte size. GH treatment to adipocytes in vitro increased zinc-α2-glycoprotein expression (>50%) and was paralleled by enhanced lipolysis and decreased triglyceride accumulation (>35%). Moreover, GH treatment improved antilipolytic action of insulin in cultured adipocytes. Most importantly, silencing zinc-α2-glycoprotein eliminated all of the GH effects on adipocyte lipid metabolism. Effects of 5-year GH supplementation therapy on adipose tissue lipid metabolism and insulin sensitivity are associated with zinc-α2-glycoprotein. Presence of this adipokine is required for the GH action on adipocyte lipid metabolism in vitro.