White Adipose Tissue Metabolism Research Articles

The autocrine role of FGF21 in cultured adipocytes.

Exposure to cold alters glucose and lipid metabolism of white and brown adipose tissue via activation of β-adrenergic receptor (ADRB). Fibroblast growth factor 21 (FGF21) has been shown to be locally released from adipose tissue upon activation of ADRBs and FGF21 increases glucose uptake in adipocytes. Therefore, FGF21 may play an autocrine role in inducing glucose uptake after β-adrenergic stimulation. To determine the putative autocrine role of FGF21, we stimulated three different types of adipocytes in vitro with Isoprenaline (Iso), an ADRB agonist, in the presence or absence of the FGF receptor (FGFR) inhibitor PD 173074. The three cell lines represent white (3T3-L1), beige (ME3) and brown (WT-1) adipocyte phenotypes, respectively. All three cells systems expressed β-klotho (KLB) and FGFR1 after differentiation and treatment with recombinant FGF21 increased glucose uptake in 3T3-L1 and WT-1 adipocytes, while no significant effect was observed in ME3. Oppositely, all three cell lines responded to Iso treatment and an increase in glucose uptake and lipolysis were observed. Interestingly, in response to the Iso treatment only the WT-1 adipocytes showed an increase in FGF21 in the medium. This was consistent with the observation that PD 173074 decreased Iso-induced glucose uptake in the WT-1 adipocytes. This suggests that FGF21 plays an autocrine role and increases glucose uptake after β-adrenergic stimulation of cultured brown WT-1 adipocytes.

Peripheral circadian rhythms in the liver and white adipose tissue of mice are attenuated by constant light and restored by time-restricted feeding.

Disturbance of circadian rhythms underlies various metabolic diseases. Constant light exposure (LL) is known to disrupt both central and peripheral circadian rhythms. Here, we attempted to determine whether the effects of LL are different between various peripheral tissues and whether time-restricted feeding restores the circadian rhythms especially in white adipose tissue (WAT). Six-week-old mice were subjected to three feeding regimes: ad libitum feeding under light/dark phase (LD), ad libitum feeding under LL cycle, and restricted feeding at night-time under LL cycle with a normal chow. After 3 weeks, we compared body weight, food intake, plasma levels of lipids and glucose, and the expression patterns of the clock genes and the genes involved in lipid metabolism in the liver and WAT. The mice kept under LL with or without time-restricted feeding were 5.2% heavier (p<0.001, n = 16) than the mice kept under LD even though the food intakes of the two groups were the same. Food intake occurred mostly in the dark phase. LL disrupted this pattern, causing disruptions in circadian rhythms of plasma levels of triglycerides (TG) and glucose. Time-restricted feeding partially restored the rhythms. LL eliminated the circadian rhythms of the expression of the clock genes as well as most of the genes involved in lipid metabolism in both liver and WAT. More notably, LL markedly decreased not only the amplitude but also the average levels of the expression of the genes in the liver, but not in the WAT, suggesting that transcription in the liver is sensitive to constant light exposure. Time-restricted feeding restored the circadian rhythms of most of the genes to various degrees in both liver and WAT. In conclusion, LL disrupted the peripheral circadian rhythms more severely in liver than in WAT. Time-restricted feeding restored the circadian rhythms in both tissues.

Markers of Metabolism in Skeletal Muscle and White Adipose Tissue are Distinctly Altered by Differing Dietary Oils in ob/ob Mice

Abstract Objectives Investigate the impact of LA-rich oil (LO) on measures of energy metabolism in a mouse model of metabolic syndrome. Methods Ob/ob mice were fed diets containing 6% wt LO, oleic acid-rich (OO) or palmitic acid-rich (PO) for 6 weeks. Body composition was measured at weeks 0 and 6. Plasma was collected at necropsy to measure adiponectin, insulin, and glucose. Grip strength and muscle fiber cross-sectional area (CSA) of total and succinate dehydrogenase-positive (SDH) fibers were quantified in quadriceps. In white adipose tissue, mRNA was measured for markers of beiging and lipid storage. Results Mice fed OO and LO diets (vs. PO diet) had reduced % adipose. There was no difference of oils on plasma adiponectin or HOMA-IR. Decreases in grip strength were observed in PO-fed mice, while OO and LO-fed mice maintained strength throughout the study. LO-fed mice exhibited smaller skeletal muscle fibers compared to the PO-fed mice. OO-fed mice had fewer intermediate-sized SDH fibers. In white adipose tissue, LO-fed mice exhibited increased PGC1a, and decreased PPARy and LPL mRNA compared to PO-fed mice. Conclusions These findings suggest that dietary LA may alter lipid mobilization and metabolism in obese mice. These preliminary results showcase the importance of future investigation of lipid storage and mitochondrial phospholipid biology in skeletal muscle. Funding Sources Funding was provided by NIH R21CA185140, Ohio Agriculture Research and Development Center and the Carol S. Kennedy Professorship. DBS received support from the AOCS Thomas H. Smouse Memorial Fellowship.

Effects of piperine on lipid metabolism in high-fat diet induced obese mice

• Piperine decreases body weight, fat weight in mice fed high-fat diet. • Piperine downregulates mRNA associated with ATE in white adipose tissue. • Piperine is more effective in visceral fat in regulating lipometabolic genes. To examine the effects of piperine on lipid metabolism in white adipose tissue of high-fat diet induced obese mice, mice were divided into CON, HFD, HFD + Pip15, and HFD + Pip30 groups (n = 10 in each group). The mice in the latter two groups received 15 and 30 mg/kg body weight of piperine, respectively. Piperine decreased body and fat weights. Piperine treatments, especially 30 mg/kg, significantly reduced adipose cell size in SAT and VAT. mRNA expressions associated with adipose tissue expansion in the HFD + Pip30 group was significantly downregulated in SAT and VAT. For lipogenesis, piperine downregulated all of determined genes in VAT. For Lipolysis, only LPL mRNA in the HFD + Pip30 group was significantly upregulated in SAT. In VAT, 30 mg/kg piperine significantly increased lipolytic enzymes and upregulated their mRNA expressions. Piperine protects against obesity and regulates the lipogenic and lipolytic genes, which is more effective in visceral fat than in subcutaneous fat.

Rev-erbαheterozygosity produces a dose-dependent phenotypic advantage in mice.

Numerous mutational studies have demonstrated that circadian clock proteins regulate behavior and metabolism. Nr1d1(Rev-erbα) is a key regulator of circadian gene expression and a pleiotropic regulator of skeletal muscle homeostasis and lipid metabolism. Loss of Rev-erbα expression induces muscular atrophy, high adiposity, and metabolic syndrome in mice. Here we show that, unlike knockout mice, Nr1d1 heterozygous mice are not susceptible to muscular atrophy and in fact paradoxically possess larger myofiber diameters and improved neuromuscular function, compared to wildtype mice. Heterozygous mice lacked dyslipidemia, a characteristic of Nr1d1 knockout mice and displayed increased whole-body fatty-acid oxidation during periods of inactivity (light cycle). Heterozygous mice also exhibited higher rates of glucose uptake when fasted, and had elevated basal rates of gluconeogenesis compared to wildtype and knockout littermates. Rev-erbα ablation suppressed glycolysis and fatty acid-oxidation in white-adipose tissue (WAT), whereas partial Rev-erbα loss, curiously stimulated these processes. Our investigations revealed that Rev-erbα dose-dependently regulates glucose metabolism and fatty acid oxidation in WAT and muscle.

Ambient fine particulate matter exposure perturbed circadian rhythm and oscillations of lipid metabolism in adipose tissues

Emerging evidence indicated that disruption of circadian rhythm (CR) induced metabolic disorders, including dysregulation of energy homeostasis and lipid dysfunction, which was associated with ambient fine particulate matter (PM2.5) as well. However, the role and mechanism of CR in PM2.5-mediated metabolic disorder remain unknown. In the present study, we investigated circadian rhythmic characteristics and explored the effect of PM2.5 on oscillating clock of lipid function and metabolism in white adipose tissue (WAT) and brown adipose tissue (BAT). C57BL/6 mice were exposed to PM2.5 in a whole-body inhalational exposure system. After 10 weeks, the expression of clock-related genes exhibits more robust CR in BAT than WAT, with the acrophase of PER2 in both types of adipose tissue being significantly decreased at ZT12 and Bmal1 increased at ZT0/24 in WAT in response to PM2.5 exposure. In addition, both CR pattern and expression levels of Sirt1 got significantly inhibited by PM2.5 exposure in WAT, accompanied with adipose dysfunction evidenced by inhibited pattern and expression levels of adipokines at the same ZT time points. Finally, a similar phase right shift from ZT4 to ZT12 in both Sirt3 and Ucp1 in BAT was induced by PM2.5 exposure. These findings indicate that disruption of the CR in adipose tissues could be an important way by which PM2.5 exposure induces metabolic disorder and provide potential targets for further investigation.

Young Persimmon Fruit Extract Suppresses Obesity by Modulating Lipid Metabolism in White Adipose Tissue of Obese Mice.

Young persimmon fruit (YPF) has recently been reported to have a regulatory effect on lipid metabolism. The aim of this study was to investigate whether the YPF aqueous extract (YPFE) exert an antiobesity effect by modulating lipid metabolism in the white adipose tissue (WAT) of obese C57BLKS/J db/db mice. YPFE (100 or 200 mg/kg body weight/day) or distilled water as a vehicle was orally administered by gavage to 12-week-old obese male db/db mice for 3 weeks (n = 7 for each group). YPFE administration significantly reduced body weight and WAT size. Furthermore, YPFE considerably reduced triglyceride and cholesterol concentrations in serum and WAT. Obese vehicle treated mice exhibited an enhanced protein expression of adipogenic and lipogenic genes. However, this increased expression was alleviated in the YPFE-fed groups, resulting in inhibition of adipogenesis and downregulation of fatty acid synthesis. In addition, there was an increase in the level of transcription factors associated with fatty acid oxidation in the YPFE-treated group. In obese mice, the expression of proteins associated with cholesterol metabolism was augmented. YPFE did not affect cholesterol synthesis, but cholesterol efflux-related proteins were significantly upregulated. YPF exerts beneficial effects on obesity by inhibiting adipogenesis and reducing lipid synthesis and accumulation by regulation of lipid-related transcription factors in the WAT of obese mice.

DEC1 regulates the rhythmic expression of PPARγ target genes involved in lipid metabolism in white adipose tissue.

Previously, we found that the basic helix-loop-helix transcriptional repressor DEC1 interacts with the PPARγ:RXRα heterodimer, a master transcription factor for adipogenesis and lipogenesis, to suppress transcription from PPARγ target genes (Noshiro et al., Genes to Cells, 2018, 23:658-669). Because the expression of PPARγ and several of its target genes exhibits circadian rhythmicity in white adipose tissue (WAT), we examined the expression profiles of PPARγ target genes in wild-type and Dec1-/- mice. We found that the expression of PPARγ target genes responsible for lipid metabolism, including the synthesis of triacylglycerol from free fatty acids (FFAs), lipid storage and the lipolysis of triacylglycerol to FFAs, oscillates in a circadian manner in WAT. Moreover, DEC1 deficiency led to a marked increase in the expression of these genes at night (Zeitgeber times 16 and 22), resulting in disruption of circadian rhythms. Serum FFA levels in wild-type mice also showed circadian oscillations, but these were disrupted by DEC1 deficiency, leading to reduced FFA levels. These results suggest that PPARγ:RXRα and DEC1 cooperatively generate the circadian expression of PPARγ target genes through PPAR-responsive elements in WAT.

Effects of the adiponectin mimetic compound ALY688 on glucose and fat metabolism in visceral and subcutaneous rat adipocytes

ABSTRACT Adiponectin regulates white adipose tissue (WAT) metabolism and promotes insulin-sensitizing and anti-atherosclerotic effects in vivo. In this context, small molecule adiponectin receptor agonists have become of great therapeutic value for the treatment of metabolic diseases. Here, we investigated the effects of the adiponectin mimetic compound ALY688 on WAT metabolism. To accomplish this, rat epididymal (Epid) and subcutaneous inguinal (Sc Ing) adipocytes were isolated and incubated with ALY688. Subsequently, several parameters of glucose and fat metabolism were assessed. ALY688 promoted AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation, enhanced glucose oxidation, and suppressed fat oxidation in adipocytes from both fat depots. ALY688 did not affect basal and insulin-stimulated rates of glucose uptake, glucose incorporation into lipids, and AKTSer473 and p38 mitogen-activated protein kinase (MAPK) phosphorylations in either Epid or Sc Ing adipocytes. ALY688 did not alter basal lipolysis in Epid and Sc Ing adipocytes, but it enhanced isoproterenol-induced lipolysis in Epid adipocytes. Adiponectin receptor 2 (AdipoR2) mRNA was the prevalent isoform expressed in all adipocytes, and Epid adipocytes displayed significantly higher AdipoR2 mRNA expression than Sc Ing adipocytes. In conclusion, ALY688 can regulate adiposity and affect glycaemic control by altering substrate portioning in the WAT in a fat depot-specific manner.

Sicyos angulatus Prevents High-Fat Diet-Induced Obesity and Insulin Resistance in Mice.

Obesity is a medical condition in which excess body fat has accumulated to a serious extent. It is a chronic disease that can lead to dyslipidemia, insulin resistance, and type 2 diabetes. In the present study, we investigated the anti-obesity effects of Sicyos angulatus (SA) extract on a high-fat diet (HFD)-induced C57BL/6J obese mice. The mice were divided into vehicle and three SA groups (25, 50, and 100 mg/kg body weight). The mice were fed a HFD with or without SA for 12 weeks. The oral administration of SA reduced body and adipose tissue weight in HFD-fed mice compared to those in the vehicle group (p<0.05). Adipocyte size and inflammation significantly decreased in the SA-administered groups in a dose-dependent manner. In particular, adipocytes larger than 5000 µm2 were remarkably reduced by around 50% in the SA-treated groups (p<0.05). In addition, SA contributes towards reducing insulin resistance (measured as the HOMA-IR index) and glucose intolerance in HFD-induced obese mice (p<0.05; Vehicle 21.5±3.1 vs. SA100 4.7±0.4). These beneficial effects of SA on obesity may be linked to the suppression of lipogenesis and stimulating energy metabolism in white adipose tissue and muscle. In white adipose tissue and muscle, the administration of SA activated AMPK pathway, leading to the inhibition of the development of pathophysiological conditions associated with obesity, including lipogenesis and inflammation. These findings suggest that SA may prevent obesity through inhibiting fat accumulation in HFD-induced obese mice. Therefore, SA is able to exert metabolic benefits in the prevention of obesity and insulin resistance.

Supplementation of Bacillus amyloliquefaciens AS385 culture broth powder containing 1-deoxynojirimycin in a high-fat diet altered the gene expressions related to lipid metabolism and insulin signaling in mice epididymal white adipose tissue.

1-Deoxynojirimycin (DNJ) has been known for its functional properties, such as its anti-hyperglycemic and anti-obesity activities. Previously, we developed a sustainable procedure to produce culture broth powder (CBP) containing DNJ using Bacillus amyloliquefaciens AS385 and demonstrated its regulatory effect on the blood glucose and lipid parameters in C57BL/6J mice. The present study was aimed to determine the molecular mechanism underlying the physiological effects of CBP intake in different concentrations (low, medium and high) towards the development of high-fat diet (HFD)-induced metabolic disorders. Ten-week consumption of CBP-supplemented diets ameliorated HFD-induced adiposity, glucose intolerance, and reduced insulin sensitivity in C57BL/6J mice. To investigate how these physiological events could take place, we analyzed the expression of genes involved in lipid metabolism and insulin signaling in epididymal white adipose tissue and found that CBP had a regulatory effect on the expression of genes related to lipid metabolism (Pparγ, Srebf1c, Acc, Scd, Hsl, Lpl), adiponectin secretion (Foxo1 and Sirt1), and insulin signaling (Irs1 and Akt2). Next, we confirmed that DNJ acted as the main active component in CBP and detected the dose-dependent DNJ uptake in vital metabolic tissues, which may explain the dose-dependent alteration in the metabolic parameters and related gene expressions following the CBP intake in this study. Collectively, our results suggested that DNJ intake in the form of CBP prevented the progression of HFD-induced metabolic disorders through regulation of adipocyte gene expression involved in lipid metabolism and insulin signaling.

White Adipose Tissue and Cancer: Impacts of Doxorubicin and Potential Co-Therapies

Abstract Background: White adipose tissue is an essential reservoir of energy that stores and releases fatty acids and secretes hormones, inflammatory cytokines and adipokines in health and cancer. The adipose tissue modulates cancer development and treatment, affecting responsiveness to chemotherapy, quality of life and survival. In addition, adipose tissue is damaged by doxorubicin, which is a non-selective anticancer drug widely used in clinical practice. Aim: This review was focused on the relevance of the white adipose tissue and how it can be affected by doxorubicin and cancer, the mechanisms involved and possible co-therapies that improve white adipose tissue functions. Scope of review: Adipose tissue complexity can influence cancer development, treatment and survival. The adipose tissue secretes adipokines that have paracrine and endocrine effects and may influence tumourigenesis, survival and quality of life in patients with cancer. The chemotherapeutic drug doxorubicin promotes deep impact on the adipose tissue, inhibiting adipogenesis and lipogenesis. Doxorubicin also causes downregulation on peroxisome proliferator-activated receptor gamma (PPARγ) and 5' adenosine monophosphate-AMP-activated protein kinase (AMPK) signalling in white adipose tissue, affecting lipid and glucose metabolism. Some alternative therapies, such as metformin, pioglitazone and physical exercise may contribute to mitigate side effects of doxorubicin. Conclusion: White adipose tissue has a complex and intricate role on cancer and is deeply affected by doxorubicin leading to a deep impact on adipose tissue function and worse quality of life. Potential co-therapies to prevent the side effects of doxorubicin should be studied to improve the quality of life of doxorubicin-treated patients.

The metabolic dysfunction of white adipose tissue induced in mice by a high-fat diet is abrogated by co-administration of docosahexaenoic acid and hydroxytyrosol.

Nutritional interventions are promising tools for the prevention of obesity. The n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) docosahexaenoic acid (DHA) modulates immune and metabolic responses while the antioxidant hydroxytyrosol (HT) prevents oxidative stress (OS) in white adipose tissue (WAT). The DHA plus HT combined protocol prevents WAT alterations induced by a high-fat diet in mice. Main related mechanisms. Male C57BL/6J mice were fed a control diet (CD; 10% fat, 20% protein, and 70% carbohydrates) or a high fat diet (HFD) (60% fat, 20% protein, and 20% carbohydrates) for 12 weeks, without and with supplementation of DHA (50 mg kg-1 day-1), HT (5 mg kg-1 day-1) or both. Measurements of WAT metabolism include morphological parameters, DHA content in phospholipids (gas chromatography), lipogenesis, OS and inflammation markers, mitochondrial activity and gene expression of transcription factors SREBP-1c, PPAR-γ, NF-κB (p65) and Nrf2 (quantitative polymerase chain reaction and enzyme-linked immunosorbent assay). The combined DHA and HT intervention attenuated obesity development, suppressing the HFD-induced inflammatory and lipogenic signals, increasing antioxidant defenses, and maintaining the phospholipid LCPUFA n-3 content and mitochondrial function in WAT. At the systemic level, the combined intervention also improved the regulation of glucose and adipokine homeostasis. The combined DHA and HT protocol appears to be an important nutritional strategy for the treatment of metabolic diseases, with abrogation of obesity-driven metabolic inflammation and recovery of a small-healthy adipocyte phenotype.

A maple syrup extract alters lipid metabolism in obese type 2 diabetic model mice

BackgroundSome polyphenols are known to improve the symptoms of diabetes. In the present study, we investigated the effects of a polyphenol-rich extract of maple syrup (MSx) on a diabetic mouse model.MethodsKK-Ay mice were fed a normal or 0.05% MSx-supplemented diet for 42 days. Body weight, food intake, serum biochemical parameters, and fecal total bile acid were measured. Gene expression of liver and epididymal white adipose tissue (WAT) and cecal microbiota were analyzed. Data were analyzed with an unpaired two-tailed Student’s t test or Welch’s t test according to the results of the F test.ResultsSerum low-density lipoprotein cholesterol levels were significantly reduced in mice that consumed MSx. Hepatic genes related to fatty acid degradation and cholesterol catabolism were upregulated in mice that consumed MSx. In contrast, the expression of genes related to lipid metabolism in WAT was unaffected by the intake of MSx. There were no significant differences between the two groups in terms of total bile acid level in the feces and the relative abundance of bacteria in the cecum.ConclusionOur results primarily indicate that MSx can help alleviate one of the symptoms of dyslipidemia.

Zinc-α2-glycoprotein promotes browning of white adipose tissue in cold-exposed male mice

The promotion of white adipose tissue (WAT) browning has emerged as a promising therapeutic target to increase energy expenditure and decrease weight gain. Zinc-α2-glycoprotein (ZAG) is a newly identified adipokine that regulates lipid metabolism. It shows high expression in brown adipose tissue (BAT), but whether ZAG plays a key role in the browning of white adipose tissue is still largely unclear. In the present study, we explored the relationship between ZAG and the browning of WAT in cold-exposed ZAG knockout (KO) mice and 3T3-L1 adipocytes with overexpressed ZAG. The results showed that cold stress induced marked accumulation of ZAG in wild type (WT) mice. Additionally, ZAG deficiency inhibited the loss of body weight and adipose tissue weight in cold stressed mice. ZAG KO mice were resistant to cold-induced expression of browning markers and energy metabolism in WAT. Furthermore, replenishment ZAG plasmid improved the reduction in cold-induced browning of WAT in ZAG KO mice. In vitro, ZAG overexpression promoted browning and mitochondrial biogenesis and increased the expression of β3-AR and P–P38 in 3T3-L1 adipocytes. These findings demonstrate that ZAG can promote the browning of white adipose tissue and can serve as a potential therapeutic target for treating metabolic diseases such as obesity.

Effects of metformin on metabolism of white and brown adipose tissue in obese C57BL/6J mice

BackgroundTo investigate effects of metformin on the regulation of proteins of white adipose tissue (WAT) and brown adipose tissue (BAT) in obesity and explore the underlying mechanisms on energy metabolism.MethodsC57BL/6J mice were fed with normal diet (ND, n = 6) or high-fat diet (HFD, n = 12) for 22 weeks. HFD-induced obese mice were treated with metformin (MET, n = 6). After treatment for 8 weeks, oral glucose tolerance test (OGTT) and hyperinsulinemic–euglycemic clamp were performed to evaluate the improvement of glucose tolerance and insulin sensitivity. Protein expressions of WAT and BAT in mice among ND, HFD, and MET group were identified and quantified with isobaric tag for relative and absolute quantification (iTRAQ) coupled with 2D LC–MS/MS. The results were analyzed by MASCOT, Scaffold and IPA.ResultsThe glucose infusion rate in MET group was increased significantly compared with HFD group. We identified 4388 and 3486 proteins in WAT and BAT, respectively. As compared MET to HFD, differential expressed proteins in WAT and BAT were mainly assigned to the pathways of EIF2 signaling and mitochondrial dysfunction, respectively. In the pathways, CPT1a in WAT, CPT1b and CPT2 in BAT were down-regulated by metformin significantly.ConclusionsMetformin improved the body weight and insulin sensitivity of obese mice. Meanwhile, metformin might ameliorate endoplasmic reticulum stress in WAT, and affect fatty acid metabolism in WAT and BAT. CPT1 might be a potential target of metformin in WAT and BAT.

Impact of discontinuation of fish oil after pioglitazone–fish oil combination therapy in diabetic KK mice

Pioglitazone is one of the thiazolidinediones (TZDs) and an insulin-sensitive drug for type 2 diabetes. In our previous study, a combination of pioglitazone and fish oil rich in n-3 polyunsaturated fatty acids (PUFAs) was shown to inhibit pioglitazone-induced side effects, such as accumulation of subcutaneous fat and body weight gain. However, the effects of the discontinuation of fish oil after combination treatment with TZD and fish oil are not clear. In this study, discontinuation of fish oil for 4 weeks showed several unfavorable effects: (1) return of plasma adiponectin level, (2) reversal of the inhibition of lipogenesis and activation of fatty acid β-oxidation in liver, (3) increase in hypertrophic adipocytes in epidydimal white adipose tissue (WAT) and (4) accumulation of lipids in brown adipose tissue (BAT). However, insulin resistance was ameliorated by pioglitazone with or without fish oil treatment and the discontinuation of fish oil. These findings indicate that discontinuation of n-3 PUFA after combination therapy with TZDs adversely affects lipid metabolism and energy homeostasis in liver, epididymal WAT and BAT.

Short-term dietary reduction of branched-chain amino acids reduces meal-induced insulin secretion and modifies microbiome composition in type 2 diabetes: a randomized controlled crossover trial

ABSTRACTBackgroundEpidemiological studies have shown that increased circulating branched-chain amino acids (BCAAs) are associated with insulin resistance and type 2 diabetes (T2D). This may result from altered energy metabolism or dietary habits.ObjectiveWe hypothesized that a lower intake of BCAAs improves tissue-specific insulin sensitivity.MethodsThis randomized, placebo-controlled, double-blinded, crossover trial examined well-controlled T2D patients receiving isocaloric diets (protein: 1 g/kg body weight) for 4 wk. Protein requirements were covered by commercially available food supplemented ≤60% by an AA mixture either containing all AAs or lacking BCAAs. The dietary intervention ensured sufficient BCAA supply above the recommended minimum daily intake. The patients underwent the mixed meal tolerance test (MMT), hyperinsulinemic-euglycemic clamps (HECs), and skeletal muscle and white adipose tissue biopsies to assess insulin signaling.ResultsAfter the BCAA− diet, BCAAs were reduced by 17% during fasting (P < 0.001), by 13% during HEC (P < 0.01), and by 62% during the MMT (P < 0.001). Under clamp conditions, whole-body and hepatic insulin sensitivity did not differ between diets. After the BCAA− diet, however, the oral glucose sensitivity index was 24% (P < 0.01) and circulating fibroblast-growth factor 21 was 21% higher (P < 0.05), whereas meal-derived insulin secretion was 28% lower (P < 0.05). Adipose tissue expression of the mechanistic target of rapamycin was 13% lower, whereas the mitochondrial respiratory control ratio was 1.7-fold higher (both P < 0.05). The fecal microbiome was enriched in Bacteroidetes but depleted of Firmicutes.ConclusionsShort-term dietary reduction of BCAAs decreases postprandial insulin secretion and improves white adipose tissue metabolism and gut microbiome composition. Longer-term studies will be needed to evaluate the safety and metabolic efficacy in diabetes patients.This trial was registered at clinicaltrials.gov as NCT03261362.

A phosphorylation-deficient mutant of retinoid X receptor α at Thr 167 alters fasting response and energy metabolism in mice

Retinoid X receptor α (RXRα) has a conserved phosphorylation motif at threonine 162 (humans) and threonine 167 (mice) within the DNA-binding domain. Here we have generated RXRα knock-in mice (RxrαT167A) bearing a single mutation of Thr 167 to alanine and examined the roles of Thr 167 in the regulation of energy metabolism within adipose, muscle, and liver tissues. RxrαT167A mice exhibited down-regulation of metabolic pathways converting glucose to fatty acids, such as acetyl-CoA carboxylase in the white adipose tissue (WAT) and ATP citrate lyase in the muscle. They also reduced gene expression for genes related to fatty acid catabolism and triglyceride synthesis in WAT and controlled heat factors such as adrenergic receptor β1 in muscles. In contrast, hepatic gluconeogenic pathways and synthetic pathways related to fatty acids remained unaffected by this mutation. Expression of multiple genes that were affected by the Thr 167 mutation in adipose tissue exhibited clear response to LG100268, a synthetic RXR agonist. Thus, the altered gene expression in mutant mice adipose appeared to be a direct effect of RXRα Thr 167 mutation and by some secondary effect of the mutation. Blood glucose levels remained normal in RxrαT167A during feeding, as observed with RXRα wild-type mice. However, RxrαT167A mice exhibited an attenuated decrease of blood glucose levels that occurred after fasting. This attenuation correlated with a concomitant down-regulation of lipid metabolism in WAT and was associated with RXRα phosphorylation at Thr 167. Thus, Thr 167 enabled RXRα to coordinate these three organs for regulation of energy metabolism and maintenance of glucose homeostasis.

Signal regulatory protein alpha initiates cachexia through muscle to adipose tissue crosstalk.

BackgroundMuscle wasting from chronic kidney disease (CKD) or from defective insulin signalling results in morbidity and, ultimately, mortality. We have identified an endogenous mediator of insulin resistance, signal regulatory protein alpha (SIRPα), which leads to cachexia in mice and is associated with cachexia in patients with CKD.MethodsWe assessed insulin signalling and mechanisms causing muscle atrophy plus white adipose tissue (WAT) metabolism in mouse models of CKD or acute diabetes (streptozotocin treatment). We then examined these factors in mice with global knockout (KO) of SIRPα and sought mediators of metabolic responses in muscle and adipose tissues of mice with either muscle‐specific or adipose tissue‐specific KO of SIRPα. Metabolic responses were confirmed in primary cultures of adipose cells.ResultsIn mice with CKD, SIRPα expression was increased in WAT (three‐fold, P < 0.05), and this was associated with precursors of cachexia: ‘pathologic browning', thermogenesis, and a two‐fold activation of protein kinase A (P < 0.05 vs. control mice) plus loss of adipose tissue mass. In contrast, mice with SIRPα global KO and CKD or acute diabetes experienced improved insulin signalling and activation of pAkt plus ‘physiologic browning' of WAT. These mice avoided losses of muscle and adipose tissues and experienced a 31% improvement in survival (P < 0.05) than did wild‐type mice with CKD. In muscle‐specific SIRPα KO mice with CKD, we uncovered that serum SIRPα levels (P < 0.05) were suppressed and were associated with improved insulin signalling both in skeletal muscles and in WAT. These changes were accompanied by physiologic WAT browning. However, in adipose‐specific SIRPα KO mice with CKD, levels of serum SIRPα were increased over two‐fold (P < 0.05), while muscle losses were minimally inhibited. Clinical implications of SIRPα signalling are suggested by our findings that include increased SIRPα expression in muscle and adipose tissues (P < 0.05 vs. healthy controls) plus higher SIRPα levels in the serum of patients with CKD (2.4‐fold, P=0.000017 vs. healthy controls).ConclusionsOur results show that SIRPα plays an important role as an anti‐insulin mediator regulating pathways to cachexia. In muscle‐specific SIRPα KO, changes in SIRPα serum levels seem to improve insulin signalling in muscle and WAT, suggesting crosstalk between muscle and adipose tissue. Therefore, targeting SIRPα may prevent cachexia in patients with CKD or acute diabetes.