Lipogenesis In Adipose Tissue Research Articles

Gpnmb secreted from liver promotes lipogenesis in white adipose tissue and aggravates obesity and insulin resistance.

Metabolism in mammals is regulated by complex interplay among different organs. Fatty acid synthesis is increased in white adipose tissue (WAT) when it is inhibited in the liver. Here we identify glycoprotein non-metastatic melanoma protein B (Gpnmb) as one liver-WAT cross-talk factor involved in lipogenesis. Inhibition of the hepatic sterol regulatory element-binding protein pathway leads to increased transcription of Gpnmb and promotes processing of the membrane protein to a secreted form. Gpnmb stimulates lipogenesis in WAT and exacerbates diet-induced obesity and insulin resistance. In humans, Gpnmb is tightly associated with body mass index and is a strong risk factor for obesity. Gpnmb inhibition by a neutralizing antibody or liver-specific knockdown improves metabolic parameters, including weight gain reduction and increased insulin sensitivity, probably by promoting the beiging of WAT. These results suggest that Gpnmb is a liver-secreted factor regulating lipogenesis in WAT, and that Gpnmb inhibition may provide a therapeutic strategy in obesity and diabetes.

OR28-1 Role of Mineralocorticoid Receptor in Metabolic Syndrome

Rates of obesity and metabolic syndrome (MetS) are at epidemic levels, leading to a rise of individuals at higher risk of developing diabetes and heart disease. Increased visceral adiposity and hyperglycemia are two shared features of MetS and excess glucocorticoids (GCs). GCs are hormones—acting primarily via the glucocorticoid receptor (GR)—commonly prescribed for inflammatory disorders, yet their use is limited due to many detrimental metabolic side effects. Additionally, GCs are used to facilitate adipogenesis in vitro, though our lab has recently shown that GR is not absolutely required for adipogenesis in vitro or in vivo. In addition to GR, GCs also bind the mineralocorticoid receptor (MR), but there are many conflicting studies as to the exact role of MR in adipogenesis. Though metabolic studies using full body MR-/- mice are impractical since these mice die within 10 days of birth due to salt wasting, we do show that MR-/- mice have white and brown adipose depots that are similar to wild-type littermates at 5 postnatal. To define the role of MR in metabolic syndrome in vivo, we created mice with an adipose-specific deletion of MR (FMRKO) by crossing MRflox/flox mice to adiponectin-cre mice. We first induced MetS by treating FMRKO and MRflox/flox control mice with corticosterone (100µg/mL) via drinking water for 4 weeks. After treatment, fat mass was increased in both FMRKO (from 3.4±0.3 to 9.3±0.7g, p<0.0001) and control mice (from 3.5±0.4 to 9.6±1.6g, p<0.0001). Additionally, fasting glucose was elevated in FMRKO (from 128±18 to 235±89mg/dL, p=0.003) and control mice (from 112±13 to 219±39mg/dL, p=0.023); however, there was no difference between groups for fat mass or blood glucose. Separately, we fed mice a high-fat diet (HFD) for 16 weeks. We saw that FMRKO mice had reduced body weight (39.3±4.2 vs 45.2±3.3g, p=0.002), primarily due to a decrease in fat mass (14.8±2.4 vs 19.2±2.3g, p<0.001) relative to control mice. While there was no difference in glucose tolerance between groups, FMRKO mice had significantly decreased plasma insulin (14.5±5.9 vs 6.4±3.3ng/mL, p=0.001). Impressively, FMRKO mice had increased oxygen consumption and energy expenditure compared to control mice. Furthermore, FMRKO had reduced expression of genes involved in adipogenesis and lipogenesis in adipose tissue, relative to control mice. Collectively, these studies provide new insight to the potential value of MR as a therapeutic target in treating conditions associated with MetS. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

De novo Lipogenesis in Adipocytes Results in the Production of Structurally Novel Signaling Lipids with Beneficial Metabolic and Anti‐inflammatory Effects

Increased de novo lipogenesis in adipose tissue is associated with enhanced insulin sensitivity in humans and rodents. Mice overexpressing the Glut4 glucose transporter in adipose tissue have elevated adipose tissue lipogenesis and increased glucose tolerance in spite of obesity and elevated circulating fatty acids. Untargeted lipidomic analysis of adipose tissue from these mice revealed marked elevation of a structurally novel class of lipids, branched Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs). More than 25 FAHFA family members, which are distinguished by different acyl chain composition, have been identified in mammalian tissues and plants. Levels of some family members such as Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs) are highly regulated in altered nutritional and metabolic states. PAHSA levels are reduced in serum and subcutaneous adipose tissue of insulin‐resistant humans and serum PAHSA levels correlate very strongly with insulin sensitivity in humans. Chronic PAHSA treatment improves glucose tolerance and insulin sensitivity in insulin‐resistant mice. PAHSAs also have anti‐inflammatory effects in states such as obesity, colitis and auto‐immune Type 1 diabetes in mice. Many effects of PAHSA are mediated through G‐protein coupled receptors. Thus, PAHSAs exert multiple beneficial metabolic and anti‐inflammatory effects in diabetes and immune‐mediated diseases. The pathways that regulate these lipids provide new opportunities for disease prevention and treatment.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

CREB‐Regulated miR‐27b Is Linked to Hepatic Insulin Resistance by Targeting Insulin/Akt Signaling

Insulin resistance (IR) is a predisposed condition of type 2 diabetes and commonly leads to fatty liver, in which hepatocytes exhibit excessive lipogenesis and gluconeogenesis. The role of microRNAs (miR) in liver‐associated IR remains largely unknown. Among microRNAs that participate in metabolic signaling, miR‐27b is a critical regulator of lipogenesis in both liver and adipose tissues; however, it is not clear if dysregulation of miR‐27b contributes to IR in liver. To address this question, we established several IR experimental models, including palmitate‐treated mouse AML12 hepatocytes, and dietary‐induced mouse fatty liver; Interestingly, miR‐27b was upregulated in all of these IR models. Furthermore, bioinformatic analysis predicted that miR‐27b targets several genes involved in Akt phosphorylation, including Pdpk1, Pik3ca (P110), Pik3r1 (P85), and Pik3cd. Based on these data, we hypothesize that miR‐27b over‐expression results in defective Akt signaling upon insulin stimulation. Indeed, over‐expression of miR‐27 in human HepaRG liver cells and mouse primary hepatocytes significantly suppressed Akt phosphorylation at both T308 and S473 residues and down‐regulated Pdpk1, Pik3r1 (P85), and Pik3ca (P110) at protein level upon insulin stimulation. Our luciferase reporter assay using 3T3 cells further demonstrated that miR‐27 directly targeted Pdpk1 and Pik3r1 3′UTR. Next, we investigated the mechanism by which miR‐27 is regulated in insulin signaling. Interestingly, we found that insulin significantly reduced miR‐27 expression below 50% of control in both HepaRG and AML12 cells. Further study on the detail mechanisms revealed that miR‐27b expression is positively regulated by cAMP response element‐binding protein (CREB), which is an IR promoter and regulated by insulin. Using HepaRG and AML12 cells, we demonstrated that miR‐27 is significantly down‐regulated by siRNA‐ or metformin‐mediated knockdown of CREB, but up‐regulated by forksolin‐induced activation of CREB. Also, miR‐27b is significantly increased when CREB is up‐regulated in mouse livers by either overnight fasting or high‐fat‐diet feeding, whereas decreased when CREB is down‐regulated in livers of mice treated with metformin. Taken together, our in vitro and in vivo data demonstrated that insulin may negatively regulate miR‐27 by repressing CREB transcriptional activity and the abnormal activation of hepatic CREB in IR animals may cause the aberrant elevation of miR‐27b to further decrease insulin sensitivity.Support or Funding InformationThis project is funded by Ministry of Science and Technology in Taiwan (Project#105‐2628‐B‐002 ‐017‐MY3)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impact of dietary starch on extrahepatic tissue lipid metabolism in farmed European (Dicentrarchus labrax) and Asian seabass (Lates calcarifer)

In aquaculture, there is high interest in substituting marine-derived with vegetable-based ingredients as energy source. Farmed carnivorous fish under high carbohydrate diets tend to increase adiposity but it remains unclear if this happens by increased lipid retention/accumulation, promotion of lipogenic pathways, or both. In order to determine the response of extrahepatic tissue to dietary starch, European (Dicentrarchus labrax) and Asian (Lates calcarifer) seabass were fed a control (low starch; LS) or experimental (high starch; HS) diet, for at least 21 days and then transferred for 6 days to saltwater enriched with deuterated water 2H2O. Incorporation of 2H-labelling follows well-defined metabolic steps, and analysis of triacylglycerols (TAG) 2H-enrichment by 2HNMR allowed evaluation of de novo lipogenesis (DNL) in muscle and visceral adipose tissue (VAT). Fractional synthetic rates for TAG-bound fatty acids and glycerol were quantified separately providing a detailed lipogenic profile. The FA profile differed substantially between muscle and VAT in both species, but their lipogenic fluxes revealed even greater differences. In European seabass, HS promoted DNL of TAG-bound FA, in muscle and VAT. High 2H-enrichment also found in muscle TAG-bound glycerol was indicative of its role on lipid cycling. In Asian seabass, HS had no effect on muscle FA composition and lipogenic flux, with no 2H-enriched TAG being detected. VAT on the other hand revealed a strong enhancement of DNL in HS-fed fish along with high TAG-bound glycerol cycling. This study consolidated the use of 2H2O as tracer for fish lipid metabolism in different tissues, under different dietary conditions and suitable to use in different fish models.

Ablation of gut microbiota alleviates obesity-induced hepatic steatosis and glucose intolerance by modulating bile acid metabolism in hamsters

Since metabolic process differs between humans and mice, studies were performed in hamsters, which are generally considered to be a more appropriate animal model for studies of obesity-related metabolic disorders. The modulation of gut microbiota, bile acids and the farnesoid X receptor (FXR) axis is correlated with obesity-induced insulin resistance and hepatic steatosis in mice. However, the interactions among the gut microbiota, bile acids and FXR in metabolic disorders remained largely unexplored in hamsters. In the current study, hamsters fed a 60% high-fat diet (HFD) were administered vehicle or an antibiotic cocktail by gavage twice a week for four weeks. Antibiotic treatment alleviated HFD-induced glucose intolerance, hepatic steatosis and inflammation accompanied with decreased hepatic lipogenesis and elevated thermogenesis in subcutaneous white adipose tissue (sWAT). In the livers of antibiotic-treated hamsters, cytochrome P450 family 7 subfamily B member 1 (CYP7B1) in the alternative bile acid synthesis pathway was upregulated, contributing to a more hydrophilic bile acid profile with increased tauro-β-muricholic acid (TβMCA). The intestinal FXR signaling was suppressed but remained unchanged in the liver. This study is of potential translational significance in determining the role of gut microbiota-mediated bile acid metabolism in modulating diet-induced glucose intolerance and hepatic steatosis in the hamster.

Chlorogenic acid alleviates obesity and modulates gut microbiota in high-fat-fed mice.

To evaluate the anti‐obesity effects of chlorogenic acid (CGA), the mice were fed a high‐fat diet (HFD) upon chlorogenic acid treatment for 6 weeks. The results showed administration of chlorogenic acid (150 mg per kg per day) remarkably promoted body loss, reduced lipid levels in plasma and altered mRNA expression of lipogenesis and lipolysis related genes in adipose tissue. Moreover, chlorogenic acid also reversed the HFD‐induced gut microbiota dysbiosis, including significantly inhibiting the growth of Desulfovibrionaceae, Ruminococcaceae, Lachnospiraceae, Erysipelotrichaceae, and raising the growth of Bacteroidaceae, Lactobacillaceae. Overall, the amelioration of HFD‐induced gut microbiota dysbiosis by chlorogenic acid may contribute, at least partially, to its beneficial effects on ameliorating HFD‐induced obesity.

Effects of feeding ethanol on growth performances, carcass characteristics, and lipid metabolism of finishing Korean cattle (Hanwoo) steers.

ObjectiveThe purpose of this study was to determine the effects of feeding ethanol on growth performances, carcass characteristics, and lipid metabolism of finishing Korean cattle (Hanwoo) steers.MethodsThirty (30) Hanwoo steers (average 25.1 months of age, body weight 660.1 kg) were assigned to three treatments: control (0% ethanol), E-3 (1.44% ethanol for 3 months), or E-5 (0.72% ethanol for 2 months followed by 1.44% ethanol for 3 months). The animals were allotted by treatment group into six pens and fed concentrate and perennial ryegrass. Ethanol (30%, v/v) was supplemented into drinking water twice a day to meet final concentrations based on average water consumption of finishing Hanwoo steers.ResultsThere were no statistical differences among the groups in final body weight, average daily gain, or carcass yield grade indices such as cold carcass weight, fat thickness, and loin area. The marbling score tended (p = 0.228) to increase with the highest score (6.7) in the E-5 group followed by 6.3 and 6.0 in E-3 and control groups, respectively. The appearance frequencies of quality grades of 1++ (the best), 1+, 1, and 2, were; 30%, 50%, 0%, and 20% for control, 10%, 80%, 10%, and 0% for E-3, and 10%, 80%, 0%, and 10% for E-5 groups, respectively, indicating improvements of quality grades by feeding ethanol. Concentrations of serum glucose tended to decrease whereas those of insulin and non-esterified fatty acid to increase by feeding ethanol (E-3 and E-5; p>0.05).ConclusionFeeding ethanol directly into drinking water of finishing Hanwoo steers stimulated lipogenesis in intramuscular adipose tissue (marbling) and thereby improved carcass quality grade. The serum metabolites results supported the hypothesis of lipolysis of existing adipose tissue, such as abdominal fats, and lipogenesis in intramuscular adipocytes.

Metabolism of glycerol in pigs fed diets containing mixed crude glycerin and β-adrenergic agonist

The optimised use of mixed crude glycerin (MCG) and ractopamine hydrochloride (RH) in diets for finishing pigs requires a better understanding of glycerol metabolism. Therefore, the present study evaluated the performance, blood parameters, metabolite concentrations in the Longissimus lumborum muscle and the activity of enzymes in the liver, subcutaneous adipose tissue and kidney of pigs fed diets containing MCG and/or RH. According to the initial weight, 64 barrows were distributed in a 4 × 2 factorial design, corresponding to four concentrations of MCG (0, 100, 150, and 200 g/kg) in diets containing 0 or 10 mg/kg of RH. There was no MCG × RH interaction for any of the evaluated parameters (P &amp;gt; 0.05). Moreover, there was no isolated effect of dietary MCG or RH on the weight gain and the blood concentrations of glucose, insulin, triacylglycerols, total cholesterol, total protein, albumin, creatinine, cortisol and lactate (P &amp;gt; 0.05). There was a higher rate of phosphorylation of glycerol in the liver, stimulation of lipogenesis in adipose tissue and a likely increase in the utilisation of glycerol by muscle fibres in response to an increased concentration of circulating glycerol from the diet (P &amp;lt; 0.05). In contrast, when the diet contained up to 200 g/kg MCG and 10 mg/kg RH, there were indications of a lower utilisation of glycerol for the synthesis of triacylglycerols in muscle, liver and adipose tissue, in addition to increased oxidation of amino acids in the liver followed by improved feed conversion of pigs (P &amp;lt; 0.05).

Elevated lipolysis in adipose tissue by doxorubicin via PPARα activation associated with hepatic steatosis and insulin resistance

Adipose dysfunction is tightly associated with hepatic insulin resistance and steatosis condition. Doxorubicin would disturb the lipid metabolism both in adipose and liver. Here we projected that doxorubicin would impede lipogenesis and elevated lipolysis in adipose tissue would elevate the circulatory lipid profile and leads to insulin resistance. Further exacerbated lipid profile in circulation would impair the lipid metabolism in hepatic tissue which leads to fatty liver condition and consequently related disease during doxorubicin treatment. Doxorubicin impairs the lipogenesis through PPARγ and augments lipolysis and fatty acid oxidation through ATGL and PPARα in adipose tissue. Increased fatty acid level by adipose tissue in circulation would translocate into the liver and dysregulates AHR, PXR, PPARγ, ATGL and Apo B,which further develop insulin resistance and hepatic steatosis condition. The findings add to the mechanistic role of association between adipose tissue dysfunction and hepatic dysfunction.

Fibroblast Growth Factor Binding Protein 3 (FGFBP3) impacts carbohydrate and lipid metabolism

Secreted FGF binding proteins (FGFBP) mobilize locally-acting paracrine FGFs from their extracellular storage. Here, we report that FGFBP3 (BP3) modulates fat and glucose metabolism in mouse models of metabolic syndrome. BP3 knockout mice exhibited altered lipid metabolism pathways with reduced hepatic and serum triglycerides. In obese mice the expression of exogenous BP3 reduced hyperglycemia, hepatosteatosis and weight gain, blunted de novo lipogenesis in liver and adipose tissues, increased circulating adiponectin and decreased NEFA. The BP3 protein interacts with endocrine FGFs through its C-terminus and thus enhances their signaling. We propose that BP3 may constitute a new therapeutic to reverse the pathology associated with metabolic syndrome that includes nonalcoholic fatty liver disease and type 2 diabetes mellitus.

Luteolin Targets the Toll-Like Receptor Signaling Pathway in Prevention of Hepatic and Adipocyte Fibrosis and Insulin Resistance in Diet-Induced Obese Mice.

This study was to investigate the protective role of luteolin on inflammation-mediated metabolic diseases, focusing on the role of luteolin in the modulation of the Toll-like receptor (TLR) signaling pathway. C57BL/6J mice were fed a normal, high-fat, or high-fat + 0.005% (w/w) luteolin diet for 16 weeks. Luteolin improved chronic low-grade inflammation by modulating the TLR signaling pathway, resulting in reduced pro-inflammatory cytokines and macrophage accumulation. A positive relationship was detected between gene expressions of Tlr5, Map2k7, Mapk12, Mapk13, and Mapk9 and lipogenesis in epididymal white adipose tissue (eWAT) of luteolin-treated mice, which was linked to attenuation of hepatic lipotoxicity by increasing free fatty acid (FFA) flux to the WAT. Luteolin prevented fibrosis by decreasing extracellular matrix accumulation and cathepsin gene expressions, while enhancing the hepatic antioxidant system. Emr1 and Ccl7, important markers inducing low-grade inflammation, were affected by advanced age and greater body weight, which were normalized by luteolin treatment. Luteolin improved insulin resistance by normalizing pancreatic islet dysfunction and differentially modulating the plasma glucagon-like peptide-1 and gastric inhibitory polypeptide levels. Our results suggest that luteolin ameliorates diet-induced obesity and its comorbidities. Overall, this study provides novel insights into the effect of luteolin on the links among adiposopathy, insulin resistance, hepatic steatosis, and fibrosis.

Impact of MR on mature adipocytes in high-fat/high-sucrose diet-induced obesity

Active glucocorticoid levels are elevated in the adipose tissue of obesity due to the enzyme 11 beta-hydroxysteroid dehydrogenase type 1. Glucocorticoids can bind and activate both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), and pharmacological blockades of MR prevent high-fat diet-induced obesity and glucose intolerance. To determine the significance of MR in adipocytes, we generated adipocyte-specific MR-knockout mice (AdipoMR-KO) and fed them high-fat/high-sucrose diet. We found that adipocyte-specific deletion of MR did not affect the body weight, fat weight, glucose tolerance or insulin sensitivity. While liver weight was slightly reduced in AdipoMR-KO, there were no significant differences in the mRNA expression levels of genes associated with lipogenesis, lipolysis, adipocytokines and oxidative stress in adipose tissues between the control and AdipoMR-KO mice. The results indicated that MR in mature adipocytes plays a minor role in the regulation of insulin resistance and inflammation in high-fat/high-sucrose diet-induced obese mice.

Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues.

De novo lipogenesis (DNL) is a complex and highly regulated process in which carbohydrates from circulation are converted into fatty acids that are then used for synthesizing either triglycerides or other lipid molecules. Dysregulation of DNL contributes to human diseases such as obesity, type 2 diabetes, and cardiovascular diseases. Thus, the lipogenic pathway may provide a new therapeutic opportunity for combating various pathological conditions that are associated with dysregulated lipid metabolism. Hepatic DNL has been well documented, but lipogenesis in adipocytes and its contribution to energy homeostasis and insulin sensitivity are less studied. Recent reports have gained significant insights into the signaling pathways that regulate lipogenic transcription factors and the role of DNL in adipose tissues. In this review, we will update the current knowledge of DNL in white and brown adipose tissues with the focus on transcriptional, post-translational, and central regulation of DNL. We will also summarize the recent findings of adipocyte DNL as a source of some signaling molecules that critically regulate energy metabolism.

Energy metabolism of white adipose tissue and insulin resistance in humans.

Insulin resistance not only occurs in obesity, but also in lipodystrophy. Although adipose tissue mass affects metabolic fluxes and participates in interorgan crosstalk, the role of energy metabolism within white adipose tissue for insulin resistance is less clear. A Medline search identified invivo studies in humans on energy and lipid metabolism in subcutaneous (SAT) and visceral adipose tissue (VAT). Studies in adipocyte cultures and transgenic animal models were included for the better understanding of the link between abnormal energy metabolism in adipose tissue and insulin resistance. The current literature indicates that higher lipolysis and lower lipogenesis in VAT compared to SAT enhance portal delivery of lipid metabolites (glycerol and fatty acids) to the liver. Thus, the lower lipolysis and higher lipogenesis in SAT favour storage of excess lipids and allow for protection of insulin-sensitive tissues from lipotoxic effects. In insulin-resistant humans, enhanced lipolysis and impaired lipogenesis in adipose tissue lead to release of cytokines and lipid metabolites, ultimately promoting insulin resistance. Adipose tissue of insulin-resistant humans also displays lower expression of proteins involved in mitochondrial function. In turn, this leads to lower availability of mitochondria-derived energy sources for lipogenesis in adipose tissue. Abnormal mitochondrial function in human white adipose tissue likely contributes to the secretion of lipid metabolites and lactate, which are linked to insulin resistance in peripheral tissues. However, the relevance of adipose tissue energy metabolism for the regulation of human insulin sensitivity remains to be further elucidated.

Dietary supplement of conjugated linoleic acids or polyunsaturated fatty acids suppressed the mobilization of body fat reserves in dairy cows at early lactation through different pathways

To investigate the metabolic changes in the adipose tissue (AT) of dairy cows under milk fat depression (MFD), 30 cows were randomly allocated to a control diet, a conjugated linoleic acid (CLA)-supplemented diet, or a high-starch diet supplemented with a mixture of sunflower and fish oil (2:1; as HSO diet) from 1 to 112 d in milk. Performance of animals, milk yield, milk composition, energy balance, and blood metabolites were measured during lactation. Quantitative PCR analyses were conducted on the AT samples collected at wk 3 and 15 of lactation. The CLA and HSO diets considerably depressed milk fat yield and milk fat content at both wk 3 and 15 in the absence of significant changes in milk protein and lactose contents. In addition, the HSO diet lowered milk yield at wk 15 and decreased dry matter intake of cows from wk 3 to 15. Compared with the control, both CLA and HSO groups showed reduced body weight loss, improved energy balance, and decreased plasma concentrations of nonesterified fatty acids and β-hydroxybutyrate at early lactation. The gene expression analyses reflected suppressed lipolysis in AT of the CLA and HSO groups compared with the control at wk 3, as suggested by the downregulation of hormone-sensitive lipase and fatty acid binding protein 4 and the upregulation of perilipin 2. In addition, the HSO diet promoted lipogenesis in AT at wk 15 through the upregulation of 1-acylglycerol-3-phosphate O-acyltransferase 2, mitochondrial glycerol-3-phosphate acyltransferase, perilipin 2, and peroxisome proliferator-activated receptor γ. The CLA diet likely regulated insulin sensitivity in AT as it upregulated the transcription of various genes involved in insulin signaling, inflammatory responses, and ceramide metabolism, including protein kinase B2, nuclear factor κ B1, toll-like receptor 4, caveolin 1, serine palmitoyltransferase long chain base subunit 1, and N-acylsphingosine amidohydrolase 1. In contrast, the HSO diet resulted in little or no change in the pathways relevant to insulin sensitivity. In conclusion, the CLA and HSO diets induced a shift in energy partitioning toward AT instead of mammary gland during lactation through the regulation of different pathways.

Lower Stearoyl-CoA Desaturase and Hormone Sensitive Lipase Gene Expression in Superficial Subcutaneous Adipose Tissue of Male, but Not Female, Patients with Type 2 Diabetes

Mitochondrial gene expression in visceral (VAT) and lipogenesis in abdominal subcutaneous adipose tissue (SAT) are lower in insulin resistance (IR). Humans with hormone sensitive lipase (HSL) gene mutations are prone to type 2 diabetes (T2D). SAT is divided into deep (DSAT) and superficial SAT (SSAT). SSAT was speculated to be protective in T2D, but gender specificity is unknown. We hypothesized lower mitochondrial efficiency as well as lower markers of lipogenesis and lipolysis in SSAT only in male T2D patients vs. glucose-tolerant humans (CON), which may characterize dysfunctional SSAT. In 20 T2D and 20 CON matched for sex, BMI and age (female/male: 6/14 per group; 32±1 vs. 31±1 kg/m2, 52±2 vs. 54±2 years), we assessed M-values by euglycemic-hyperinsulinemic clamps, liver fat content (HCL) and VAT by MRS. In biopsies of SSAT, mitochondrial oxidative capacity was measured by respirometry, lipogenesis assessed from stearoyl-CoA desaturase (SCD) mRNA, lipolysis from adipocyte triglyceride lipase (ATGL) and HSL mRNA by RTqPCR. The insulin resistant T2D had 63% and 22% higher HCL (p&amp;lt;0.01) and VAT (p&amp;lt;0.05) than CON. In SSAT, T2D featured 20%, 50%, 70%, 49% reductions in oxidative capacity, SCD, ATGL and HSL mRNA (all p&amp;lt;0.05). Gender segregated analyzes showed higher oxidative capacity only in females, whereas only ATGL was also lower in female T2D vs. CON. In T2D, VAT was 22% lower (p&amp;lt;0.01) and HSL mRNA 70% higher (both p&amp;lt;0.001) in female than in male participants. In conclusion, lower lipogenesis and lipolysis in SSAT of male T2D patients may lead to inadequate lipid storage in SSAT, thereby promoting ectopic fat storage as HCL and VAT. Disclosure K. Bódis: None. J. Lundbom: None. T. Jelenik: None. D.F. Markgraf: None. A. Strom: None. O.P. Zaharia: None. Y. Karusheva: None. V. Burkart: None. K. Müssig: None. Y. Kupriyanova: None. M. Ouni: None. J. Hwang: None. D. Ziegler: None. A. Schuermann: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. J. Szendroedi: None.

Monomethyl Branched Chain Fatty Acids link Mitochondrial Amino Acid Metabolism and Adipose Tissue Lipogenesis to Fatty Acid Diversity

BCAA's are important substrates for protein synthesis and bioenergetics in mammals, and this metabolic pathway is dysregulated in various disease states. Fatty acid biosynthesis occurs in many tissues, but the balance of lipogenesis in liver and adipose tissue is disturbed in the context of obesity and metabolic syndrome. Here, using in vitro and in vivo stable isotope tracing we demonstrate that these pathways are linked within adipose tissue, where mammalian FAS produces monomethyl branched chain fatty acids (mmBCFAs). BCAA catabolic flux and short chain fatty acids from the gut microbiome initiate fatty acid synthesis in brown and beige adipocytes to influence the diversity of fatty acids present in the body. Diet‐induced obesity decreases BCAA catabolism and adipose tissue de novo lipogenesis such that mmBCFAs are the most reduced fatty acid species detected and mmBCFA abundance correlates negatively with markers of non‐alcoholic steatohepatitis. These results highlight the origin and regulation of mmBCFAs in mammals, which may play functional roles in metabolic homeostasis, nutrient sensing, and membrane function in human disease.Support or Funding InformationAjinomoto Innovation Alliance Program Grant.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Chitin Oligosaccharide Modulates Gut Microbiota and Attenuates High-Fat-Diet-Induced Metabolic Syndrome in Mice.

Gut microbiota has been proved to be an indispensable link between nutrient excess and metabolic syndrome, and chitin oligosaccharide (NACOS) has displayed therapeutic effects on multiple diseases such as cancer and gastritis. In this study, we aim to confirm whether NACOS can ameliorate high-fat diet (HFD)-induced metabolic syndrome by rebuilding the structure of the gut microbiota community. Male C57BL/6J mice fed with HFD were treated with NACOS (1 mg/mL) in drinking water for five months. The results indicate that NACOS improved glucose metabolic disorder in HFD-fed mice and suppressed mRNA expression of the protein regulators related to lipogenesis, gluconeogenesis, adipocyte differentiation, and inflammation in adipose tissues. Additionally, NACOS inhibited the destruction of the gut barrier in HFD-treated mice. Furthermore, 16S ribosome RNA sequencing of fecal samples demonstrates that NACOS promoted the growth of beneficial intestinal bacteria remarkably and decreased the abundance of inflammogenic taxa. In summary, NACOS partly rebuilt the microbial community and improved the metabolic syndrome of HFD-fed mice. These data confirm the preventive effects of NACOS on nutrient excess-related metabolic diseases.

High phosphate diet suppresses lipogenesis in white adipose tissue.

Excessive phosphate intake has been positively associated with renal and vascular dysfunction, conversely negatively associated with body fat accumulation. We investigated the effect of a high-phosphate diet on the expression of lipid metabolic genes in white adipose tissue and liver. Male 8-week-old Sprague–Dawley rats were fed a control diet containing 0.6% phosphate or a high-phosphate diet containing 1.5% phosphate for 4 weeks. In comparison to the control group, the HP group showed a significantly lower body fat mass and fasting plasma insulin level alongside decreased lipogenic and increased lipolytic gene expression in visceral fat. Additionally, the expression of genes involved in hepatic lipogenesis, hepatic glycogenesis, and triglyceride accumulation decreased in the high-phosphate group. Exogenous phosphate, parathyroid hormone, and fibroblast growth factor 23 did not directly affect the expression of lipolytic or lipogenic genes in 3T3-L1 adipocytes and HepG2 hepatocytes. Thus, the high-phosphate diet suppressed the activity of white adipose tissue by increasing lipolytic gene expression and decreasing lipogenic gene expression. These effects could have been caused by the lowered fasting plasma insulin level that occurred in response to the high-phosphate diet, but were not directly caused by the increases in plasma phosphate or phosphaturic hormones.