Fat Deposition In Skeletal Muscle Research Articles

TMT-labeled quantitative malonylome analysis on the longissimus dorsi muscle of Laiwu pigs reveals the role of ACOT7 in fat deposition

The Laiwu pig is an indigenous fatty pig breed distributed in North China, characterized by an extremely high level of intramuscular fat (IMF) content (9% ∼ 12%), but the regulatory mechanism underlying intramuscular fat deposition in skeletal muscle is still unknown. In this study, the TMT-labeled quantitative malonylome of the longissimus dorsi muscle in Laiwu pigs at the fastest IMF deposition stage (240 d vs 120 d) was compared to analyze the molecular mechanism of IMF variation in pigs. In Laiwu pigs aged 240 days/120 days, we identified 291 malonylated lysine sites across 188 proteins in the longissimus dorsi muscle. Among these, 38 sites across 31 proteins exhibited differential malonylation. Annotation analysis and enrichment analysis were performed for differentially malonylated proteins (DMPs). These DMPs were mainly clustered into 12 GO functional categories accounting for 5 biological processes, 4 cellular components and 3 molecular functions, and 2 signaling pathways by KEGG enrichment analysis. The function of differentially malonylated protein ACOT7 in the process of fat deposition was further investigated during the differentiation of 3 T3-L1 cells. The results showed that the protein level of ACOT7 in 3 T3-L1 cells decreased but the malonylated level of ACOT7 increased significantly. The malonyl-CoA that is synthesized by ACSF3 affected the malonylation level of ACOT7 in 3 T3-L1 cells. SignificanceThe intramuscular fat (IMF) content, by affecting sensory quality traits of meat, such as tenderness, flavor and juiciness, plays an important role in meat quality. Using TMT-based quantitative malonylated proteome analysis, we identified malonylated proteins in LD muscle samples in two stages (120 d and 240 d) of development and further identified differentially malonylated proteins, such as SLC25A4, ANXA5, TPM3 and ACOT7, that are associated with intramuscular fat deposition and fat metabolism in pigs. These differentially malonylated proteins could serve as candidates for elucidating the molecular mechanism of IMF deposition in pigs. In addition, we found that the malonyl-CoA in 3 T3-L1 cells is mainly synthesized by ACSF3, affecting the malonylated level of ACOT7. The study provides some data concerning the role of protein malonylation in regulating the variation in porcine IMF content.

Association Between Insulin Resistance and Myosteatosis Measured by Abdominal Computed Tomography.

Ectopic fat deposition in skeletal muscle, termed myosteatosis, is a key factor in developing insulin resistance. This work aimed to evaluate the association between insulin resistance and myosteatosis in a large Asian population. A total of 18 251 participants who had abdominal computed tomography were included in this cross-sectional study. Patients were categorized into 4 groups according to quartiles of Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). The total abdominal muscle area (TAMA) at the L3 vertebral level was segmented into normal-attenuation muscle area (NAMA), low-attenuation muscle area (LAMA), and intermuscular adipose tissue (IMAT). The absolute values of TAMA, NAMA, LAMA, and IMAT and the ratios of NAMA/BMI, LAMA/BMI, and NAMA/TAMA were used as myosteatosis indices. The absolute values of TAMA, NAMA, LAMA, and IMAT appeared to increase with higher HOMA-IR levels, and LAMA/BMI showed a similar upward trend. Meanwhile, the NAMA/BMI and NAMA/TAMA index showed downward trends. As HOMA-IR levels increased, the odds ratios (ORs) of the highest quartile of NAMA/BMI and NAMA/TAMA index decreased and that of LAMA/BMI increased. Compared with the lowest HOMA-IR group, the adjusted ORs (95% CI) in the highest HOMA-IR group for the lowest NAMA/TAMA quartile were 0.414 (0.364-0.471) in men and 0.464 (0.384-0.562) in women. HOMA-IR showed a negative correlation with NAMA/BMI (r = -0.233 for men and r = -0.265 for women), and NAMA/TAMA index (r = -0.211 for men and r = -0.214 for women), and a positive correlation with LAMA/BMI (r = 0.160 for men and r = 0.119 for women); P was less than .001 for all. In this study, a higher HOMA-IR level was significantly associated with a high risk of myosteatosis.

1699-P: Association between Insulin Resistance and Myosteatosis Measured by Abdominal Computed Tomography

Background: Ectopic fat deposition in skeletal muscle, termed myosteatosis, is a key factor in developing insulin resistance. We aimed to evaluate the association between insulin resistance and myosteatosis in a large Asian population. Methods: A total of 18,251 participants who had abdominal computed tomography from 2012 to 2013 were included. The total abdominal muscle area (TAMA) at the L3 vertebral level was segmented into normal-attenuation muscle area (NAMA), low-attenuation muscle area (LAMA), and intramuscular adipose tissue (IMAT). The ratios of NAMA/BMI, LAMA/BMI, and NAMA/TAMA were used as myosteatosis indices. Results: NAMA/BMI and NAMA/TAMA index showed downward trends with higher HOMA-IR levels, while LAMA/BMI showed upward trends. As HOMA-IR levels increased, the odds ratios (ORs) of the highest quartile of NAMA/BMI and NAMA/TAMA index decreased and that of LAMA/BMI increased. Compared with the lowest HOMA-IR group, the adjusted ORs (95% confidence intervals [CI]) in the highest HOMA-IR group for the lowest NAMA/TAMA quartile were 0.414 (0.364-0.471) in males and 0.464 (0.384-0.562) in females. HOMA-IR showed a negative correlation with NAMA/TAMA index (r = -0.211 for men and r = -0.214 for women, p <0.001 for both). Conclusion: A higher HOMA-IR level was significantly associated with a high risk of myosteatosis. Disclosure M.Kim: None. Y.Cho: None. H.Jung: None. C.Jung: None. J.Won: None. J.Park: None. H.Kim: None. W.Lee: None.

The involvement of FATP1 regulating skeletal muscle fat deposition in stressed broilers was affected by fatty acid substrates.

Fatty acid transport protein 1 (FATP1), plays a major role in the transport and uptake of fatty acids into cells. The effect of FATP1 on the regulation of skeletal muscle fat uptake and deposition in stressed broiler chickens was investigated both in vivo and in vitro, and the effect of different fatty acid substrates were also included. Dexamethasone (DEX), a synthetic glucocorticoid (GCs), was employed to induce a hyper glucocorticoid milieu and simulate stress. The in vivo results showed that DEX would increase the mRNA expression of FATP1 and fat deposition in muscle tissues (P < 0.05), the very-low-density lipoprotein (VLDL) and insulin (INS) levels were significantly increased in the plasma by DEX (P < 0.05), and the mRNA levels of the glucocorticoid receptor (GR), adiponectin receptor (ADPNR) and peroxisomal proliferator-activated receptor α (PPARα) in thigh were also up-regulated by DEX (P < 0.05). In vitro experiment, DEX did not affect the myoblast fat deposition and PPARα and FATP1 expressions without the external fatty acid (P > 0.05). Under PA pre-treatment, both myoblast fatty acid uptake and fat deposition were promoted by DEX treatment (P < 0.05), and the effects of DEX on the gene expressions of GR, ADPNR, PPARα and FATP1 were upregulated first and then downregulated as the dose of DEX increases; while under OA pre-treatment, the myoblast fat deposition was not affected by DEX (P > 0.05), the fatty acid uptake was decreased by DEX at 500 nM compared to control (P < 0.05). When GR and PPARα were, respectively inhibited by specific inhibitors RU486 and GW6471, the effects of DEX on fatty acid uptake were reversed for PA pre-treated myoblasts (P < 0.05) but not for OA pre-treated myoblasts (P > 0.05). These results indicate that FATP1 regulation by GCs was affected by fatty acid substrate - saturated fatty acids were favorable for fat uptake and deposition, while unsaturated fatty acids were not. GCs may affect the ADPNR-PPARα-FATP1 pathway by binding to its receptors, thus regulating the uptake of saturated fatty acids into myoblasts.

Progressive Sarcopenia Correlates with Poor Response and Outcome to Immune Checkpoint Inhibitor Therapy.

Background: Immune checkpoint inhibitors (ICIs) represent a new therapeutic standard for an increasing number of tumor entities. Nevertheless, individual response and outcome to ICI is very heterogeneous, and the identification of the ideal ICI candidate has remained one of the major issues. Sarcopenia and the progressive loss of muscle mass and strength, as well as muscular fat deposition, have been established as negative prognostic factors for a variety of diseases, but their role in the context of ICI therapy is not fully understood. Here, we have evaluated skeletal muscle composition as a novel prognostic marker in patients undergoing ICI therapy for solid malignancies. Methods: We analyzed patients with metastasized cancers receiving ICI therapy according to the recommendation of the specific tumor board. Routine CT scans before treatment initialization and during ICI therapy were used to assess the skeletal muscle index (L3SMI) as well as the mean skeletal muscle attenuation (MMA) in n = 88 patients receiving ICI therapy. Results: While baseline L3SMI and MMA values were unsuitable for predicting the individual response and outcome to ICI therapy, longitudinal changes of the L3SMI and MMA (∆L3SMI, ∆MMA) during ICI therapy turned out to be a relevant marker of therapy response and overall survival. Patients who responded to ICI therapy at three months had a significantly higher ∆L3SMI compared to non-responders (−3.20 mm2/cm vs. 1.73 mm2/cm, p = 0.002). Moreover, overall survival (OS) was significantly lower in patients who had a strongly decreasing ∆L3SMI (<−6.18 mm2/cm) or a strongly decreasing ∆MMA (<−0.4 mm2/cm) during the first three month of ICI therapy. Median OS was only 127 days in patients with a ∆L3SMI of below −6.18 mm2/cm, compared to 547 days in patients with only mildly decreasing or even increasing ∆L3SMI values (p < 0.001). Conclusion: Both progressive sarcopenia and an increasing skeletal muscle fat deposition are associated with poor response and outcome to ICI therapy, which might help to guide treatment decisions during ICI therapy.

Abdominal fat distribution modulates the metabolic effects of exogenous ketones in individuals with new-onset prediabetes after acute pancreatitis: Results from a randomized placebo-controlled trial.

Exogenous ketone supplementation is emerging as a nutritional intervention that beneficially affects blood glucose control. We hypothesized that varying abdominal fat phenotypes play a role in the effect of exogenously induced ketosis. The aim was to investigate whether intra-abdominal fat distribution modulates the effect of exogenous ketones on glucoregulatory peptides in new-onset prediabetes. Eighteen individuals with new-onset prediabetes after acute pancreatitis were randomized to receive a ketone monoester supplement or placebo in a crossover fashion. All participants underwent magnetic resonance imaging on a 3T scanner to determine their abdominal fat phenotypes. They were non-exclusively categorized as low adiposity or high adiposity phenotypes based on their abdominal and ectopic fat distribution (regardless of body mass index and waist circumference). Blood samples were analyzed for glucoregulatory peptides. Total area under the curve (AUC) over 150min was calculated for each analyte. The total AUCs for insulin and C-peptide were significantly higher after ketone supplementation in individuals with high intra-pancreatic fat deposition, skeletal muscle fat deposition, and subcutaneous fat volume; and low visceral fat volume and intra-hepatic fat deposition. The total AUC for glucose-dependent insulinotropic peptide was significantly higher after ketone supplementation in individuals with high intra-pancreatic fat deposition, skeletal muscle fat deposition, subcutaneous fat volume, and visceral fat volume. The total AUC for glucagon-like peptide-1 was not associated with any adiposity phenotype. Individuals with high depositions of intra-pancreatic fat, skeletal muscle fat, subcutaneous fat may not achieve favorable outcomes of blood glucose control following ketone supplementation. Abdominal fat distribution is an important factor in the pathogenesis of new-onset prediabetes and it may influence the effectiveness of nutritional strategies designed for these individuals. REGISTERED UNDER CLINICALTRIALS. NCT03889210.

Targeted overexpression of PPARγ in skeletal muscle by random insertion and CRISPR/Cas9 transgenic pig cloning enhances oxidative fiber formation and intramuscular fat deposition.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a master regulator of adipogenesis and lipogenesis. To understand its roles in fiber formation and fat deposition in skeletal muscle, we successfully generated muscle-specific overexpression of PPARγ in two pig models by random insertion and CRISPR/Cas9 transgenic cloning procedures. The content of intramuscular fat was significantly increased in PPARγ pigs while had no changes on lean meat ratio. PPARγ could promote adipocyte differentiation by activating adipocyte differentiating regulators such as FABP4 and CCAAT/enhancer-binding protein (C/EBP), along with enhanced expression of LPL, FABP4, and PLIN1 to proceed fat deposition. Proteomics analyses demonstrated that oxidative metabolism of fatty acids and respiratory chain were activated in PPARγ pigs, thus, gathered more Ca2+ in PPARγ pigs. Raising of Ca2+ could result in increased phosphorylation of CAMKII and p38 MAPK in PPARγ pigs, which can stimulate MEF2 and PGC1α to affect fiber type and oxidative capacity. These results support that skeletal muscle-specific overexpression of PPARγ can promote oxidative fiber formation and intramuscular fat deposition in pigs.

Daidzein stimulates fatty acid-induced fat deposition in C2C12 myoblast cells via the G protein-coupled receptor 30 pathway

Fat deposition in skeletal muscle is an important aspect of improving meat quality. Isoflavones can promote animal anabolism, but whether and how they regulate muscle fat deposition remain largely unclear. In this study, we explored the role and corresponding molecular mechanism of one of the major isoflavones, daidzein, in fat deposition in C2C12 myoblast cells. In the absence of fatty acids (FAs), daidzein did not promote triglyceride synthesis and lipid droplet formation in cells but increased sterol regulatory element-binding protein 1c (SREBP-1c) expression and maturation. In the presence of FAs, daidzein enhanced FAs-induced fat deposition and the SREBP-1c signaling. Daidzein promoted FAs-induced nuclear factor κB1 (NFκB1) phosphorylation and activated the SREBP-1c signaling in a PI3K-dependent manner. G protein-coupled receptor 30 (GPR30) knockdown but not estrogen receptor α (ERα) knockdown blocked the stimulation of daidzein on the PI3K-NFκB1-SREBP-1c signaling pathway, while both knockdown did not affect the stimulation of FAs on this signaling. qRT-PCR and ChIP-qPCR further detected that daidzein stimulated NFκB1-targeted SREBP-1c transcription. Daidzein did not affect ERα expression in cells, but it stimulated GPR30 expression and cytoplasmic localization. These results reveal that daidzein promotes FAs-induced fat deposition through the GPR30 signaling in C2C12 myoblast cells.

Reduced Skeletal Muscle Volume and Increased Skeletal Muscle Fat Deposition Characterize Diabetes in Individuals after Pancreatitis: A Magnetic Resonance Imaging Study.

Background: Skeletal muscle has been implicated in the pathogenesis of type 2 diabetes but it has never been investigated in diabetes after pancreatitis. The aim was to investigate the relationship between psoas muscle volume (PMV) and diabetes in individuals after pancreatitis, as well as its associations with ectopic fat phenotypes and insulin traits. Methods: Individuals after an attack of pancreatitis and healthy individuals were studied in a cross-sectional fashion. All participants underwent magnetic resonance imaging, based on which PMV, skeletal muscle fat deposition (SMFD), as well as liver and intra-pancreatic fat depositions were derived. Fasting and postprandial blood samples were collected to calculate indices of insulin sensitivity and secretion. Linear regression analyses were conducted, adjusting for possible confounders (age, sex, body composition, comorbidities, use of insulin, and others). Results: A total of 153 participants were studied. PMV was significantly decreased in the diabetes group compared with healthy controls (β = −30.0, p = 0.034 in the most adjusted model). SMFD was significantly inversely associated with PMV (β = −3.1, p < 0.001 in the most adjusted model). The Matsuda index of insulin sensitivity was significantly directly associated with PMV (β = 1.6, p = 0.010 in the most adjusted model). Conclusions: Diabetes in individuals after pancreatitis is characterized by reduced PMV. Reduced PMV is associated with increased SMFD and decreased insulin sensitivity in individuals after pancreatitis.

Associations Between Cannabis Use, Abdominal Fat Phenotypes and Insulin Traits.

BackgroundGeneral obesity has been linked to dysregulation of the endocannabinoid system in humans. However, there is a lack of studies on the relationship between cannabis use and specific abdominal fat phenotypes. The aim was to investigate the associations between cannabis use and magnetic resonance imaging-derived fat phenotypes, as well as indices of insulin sensitivity and insulin secretion.MethodsIn this cross-sectional study, magnetic resonance imaging was used to quantify subcutaneous fat volume (SFV), visceral fat volume (VFV), intra-hepatic fat deposition (IHFD), intra-pancreatic fat deposition (IPFD) and skeletal muscle fat deposition (SMFD) by two independent observers. Insulin sensitivity was determined based on HOMA-IS, Raynaud index and Matsuda index, whereas insulin secretion was determined based on HOMA-β, insulinogenic index 30’ and insulinogenic index 60’. A validated questionnaire was used to ascertain participants’ cannabis use. Linear regression models were constructed, adjusting for demographics, glycated hemoglobin, physical activity, tobacco smoking and alcohol consumption.ResultsA total of 120 individuals were included. Cannabis use explained 9.2% of variance in IHFD, 4.4% in SMFD, 3.4% in VFV, 0.4% in SFV and 0.2% in IPFD. Regular cannabis users had significantly greater IHFD compared with never users, in both the unadjusted (P = 0.002) and all adjusted (P = 0.002; P = 0.008) analyses. The other fat phenotypes did not differ significantly between either regular or non-regular users compared with never users. Regular cannabis users had significantly greater insulin secretion (as defined by the insulinogenic index 60’) compared with never users, in both the unadjusted (P = 0.049) and all adjusted (P = 0.003; P = 0.004) analyses. Cannabis use explained 20.3% of variance in the insulinogenic index 60’, but was not significantly associated with the other indices of insulin secretion. There were no significant differences in indices of insulin sensitivity in either regular or non-regular cannabis users compared with never users.ConclusionRegular cannabis use may be a risk factor for non-alcoholic fatty liver disease (but not IPFD) and may alter the neuromodulation of insulin secretion. Further investigations are now warranted to elucidate the mechanisms underlying these associations.

TMT-labeled quantitative proteomic analyses on the longissimus dorsi to identify the proteins underlying intramuscular fat content in pigs

The Laiwu pig is famous for its excessively extremely high level of intramuscular fat content (IMF), however, the exact regulatory mechanism underlying intramuscular fat deposition in skeletal muscle is still unknown. As an economically important trait in pigs, IMF is controlled by multiple genes and biological pathways. In this study, we performed an integrated transcriptome-assisted TMT-labeled quantitative proteomic analysis of the longissimus dorsi (LD) muscle in Laiwu pigs at the fastest IMF deposition stage and identified 5074 unique proteins and 52 differentially abundant proteins (DAPs) (>1.5-fold cutoff, p < .05). These DAPs were hierarchically clustered in the LD muscle over two developmental stages from 120 d to 240 d. A comparison between transcriptomic (mRNA) and proteomic data revealed two differentially expressed genes corresponding to the DAPs. Changes in the levels of the nine proteins were further analyzed using RT-qPCR and parallel reaction monitoring (PRM). The proteins identified in this study could serve as candidates for elucidating the molecular mechanism of IMF deposition in pigs. SignificanceThe intramuscular fat content (IMF) refers to the amount of fat within muscles and plays an important role in meat quality by affecting meat quality-related traits, such as tenderness, juiciness and flavor. Using the integrated transcriptome-assisted TMT-labeled quantitative proteomic approach to characterize changes in the proteomic profile of the longissimus dorsi muscle, we identified differentially abundant proteins, such as ALDH1B1, OTX2, AnxA6 and Zfp512, that are associated with intramuscular fat deposition and fat biosynthesis in pigs. These proteins could serve as candidates for elucidating the molecular mechanism of IMF deposition in pigs.

PO-305 An 8-week, low carbohydrate, high fat, ketogenic diet enhanced exercise capacity through improved ketolysis and lipolysis in mice

PO-305 An 8-week, low carbohydrate, high fat, ketogenic diet enhanced exercise capacity through improved ketolysis and lipolysis in mice

Impact of myosteatosis on skeletal muscle volume loss in patients with chronic liver disease.

Severe muscle volume loss is a recognized negative prognostic factor in patients with chronic liver disease. However, the effect of skeletal muscle fat deposition, referred to as myosteatosis on muscle volume loss remains unclear. The aim of this study was to investigate the relationships between myosteatosis and skeletal muscle volume loss. We enrolled 362 patients with chronic liver disease (186 men, 176 women; mean age 68.4±10.0years, 94 with cirrhosis) who underwent liver biopsy and computed tomography scanning between January 2013 and February 2017. A transverse computed tomography image of each scan at the third lumbar vertebra was used to evaluate skeletal muscle tissues. Prevalence of skeletal muscle volume loss and myosteatosis were 36% and 82%, respectively. Of those with skeletal muscle volume loss, 93% have concomitant myosteatosis. Univariate analysis revealed that higher age, female, lower body mass index (BMI), higher serum albumin, lower alanine aminotransferase (ALT), lower gamma-glutamyl transpeptidase, lower total bilirubin, lower α-fetoprotein, lower skeletal muscle attenuation, and liver steatosis were significantly associated with skeletal muscle volume loss. Multivariate logistic regression analysis confirmed that lower BMI (odds ratio [OR] 5.26, 95% confidence interval [CI], 3.21-8.54; P<0.001), presence of myosteatosis (OR, 2.82; 95% CI, 1.26-6.30; P<0.001), lower ALT (OR, 2.04; 95% CI, 1.18-3.52; P=0.010), and female (OR, 1.71; 95% CI, 1.04-2.28; P=0.034) were significant independent factors associated with skeletal volume loss. Myosteatosis, low BMI, low ALT, and female are associated with skeletal muscle volume loss in patients with chronic liver disease.

Ectopic Fat Deposition on Insulin Sensitivity: Correlation of Hepatocellular Lipid Content and M Value.

Purpose. This study aimed to explore the relationship among insulin sensitivity and ectopic fat depots in participants with different glucose status. Methods. Fifty-nine men and women were enrolled in this study: 29 with normal glucose tolerance (NGT), 17 with impaired glucose tolerance (IGT), and 13 with type 2 diabetes mellitus (T2DM). All participants underwent a hyperinsulinemic-euglycemic clamp to assess the insulin sensitivity index (M value) and magnetic resonance imaging to measure the hepatocellular lipid content (HCL), skeletal muscle fat content including intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) of tibialis anterior (ta), and soleus muscle (sol). Results. The M value of NGT group was higher than those of IGT and T2DM groups (P = 0.001). Participants with T2DM had the highest HCL and IMCL (ta) compared with those in NGT and IGT groups (P = 0.001). The M value had an inverse relationship with HCL (r = −0.789, P = 0.001), IMCL (sol) (r = −0.427, P = 0.002), and IMCL (ta) (r = −0.419, P = 0.002). Stepwise linear regression analysis showed that HCL (standardized β = −0.416; P = 0.001) had an independent relationship with M value. Conclusions. Hepatocellular lipid content deposition happens earlier than skeletal muscle fat deposition. HCL is an independent risk factor for insulin resistance and may be used to evaluate the risk of developing T2DM as a noninvasive marker of insulin sensitivity index.

Ethnic differences in hepatic and systemic insulin sensitivity and their associated determinants in obese black and white South African women.

There is evidence to suggest that ectopic fat deposition in liver and skeletal muscle may differ between black and white women resulting in organ-specific differences in insulin sensitivity. Accordingly, the aim of the study was to examine ethnic differences in hepatic and peripheral insulin sensitivity, and the association with hepatic and skeletal muscle lipid content, and skeletal muscle gene expression. In a cross-sectional study including 30 obese premenopausal black and white women, body composition (dual energy x-ray absorptiometry), liver fat and skeletal muscle (soleus and tibialis anterior) fat accumulation (proton-magnetic resonance spectroscopy), skeletal muscle gene expression, insulin sensitivity (two-step isotope labelled, hyperinsulinaemic-euglycaemic clamp with 10 mU m(-2) min(-1) and 40 mU m(-2) min(-1) insulin infusions), and serum adipokines were measured. We found that, although whole-body insulin sensitivity was not different, obese white women presented with lower hepatic insulin sensitivity than black women (% suppression of endogenous glucose production [% supp EGP], median [interquartile range (IQR)]: 17 [5-51] vs 56 [29-100] %, p = 0.002). While liver fat tended to be lower (p = 0.065) and skeletal muscle fat deposition tended to be higher (p = 0.074) in black compared with white women, associations with insulin sensitivity were only observed in black women (% supp EGP vs liver fat: r = -0.57, p < 0.05 and % supp EGP vs soleus fat: r = -0.56, p < 0.05). These findings may suggest that black women are more sensitive to the effects of ectopic lipid deposition than white women.

Analysis of differentially expressed genes and signaling pathways related to intramuscular fat deposition in skeletal muscle of sex-linked dwarf chickens.

Intramuscular fat (IMF) plays an important role in meat quality. However, the molecular mechanisms underlying IMF deposition in skeletal muscle have not been addressed for the sex-linked dwarf (SLD) chicken. In this study, potential candidate genes and signaling pathways related to IMF deposition in chicken leg muscle tissue were characterized using gene expression profiling of both 7-week-old SLD and normal chickens. A total of 173 differentially expressed genes (DEGs) were identified between the two breeds. Subsequently, 6 DEGs related to lipid metabolism or muscle development were verified in each breed based on gene ontology (GO) analysis. In addition, KEGG pathway analysis of DEGs indicated that some of them (GHR, SOCS3, and IGF2BP3) participate in adipocytokine and insulin signaling pathways. To investigate the role of the above signaling pathways in IMF deposition, the gene expression of pathway factors and other downstream genes were measured by using qRT-PCR and Western blot analyses. Collectively, the results identified potential candidate genes related to IMF deposition and suggested that IMF deposition in skeletal muscle of SLD chicken is regulated partially by pathways of adipocytokine and insulin and other downstream signaling pathways (TGF-β/SMAD3 and Wnt/catenin-β pathway).

Metabolic effects of telmisartan in subjects with abdominal obesity: A prospective randomized controlled trial

Background. Abdominal obesity, characterized by ectopic fat deposition in skeletal muscle and liver tissue, has been associated with insulin resistance and increased risk for type 2 diabetes mellitus. The aim of this study was to evaluate whether treatment with the angiotensin II type 1 (AT-1) receptor blocker telmisartan can reduce intramyocellular lipid (IMCL) and hepatic fat storage, thereby improving insulin sensitivity among individuals with abdominal obesity. Methods. Ninety-five adults with abdominal obesity (body mass index ≥ 30 kg/m2 and waist circumference > 102 cm in men and > 88 cm in women) were randomized to double-blind treatment with telmisartan or placebo for 24 weeks. Following 4 weeks of 80 mg telmisartan per day, the dose was increased to 160 mg telmisartan for the duration of the study. Soleus muscle IMCL and liver fat content were assessed by 1H-magnetic resonance imaging (1H-MRI) spectroscopy. Secondary outcomes included changes in body composition, plasma lipids, glucose profiles, insulin sensitivity, beta-cell function and total adiponectin levels. Results. There was no significant effect of telmisartan in abdominally obese individuals consuming either a low or high glycemic diet, on IMCL content (5.73 ± 1.11 vs 6.11 ± 1.11; p = 0.13) or liver fat (0.08 ± 0.05 vs 0.09 ± 0.05; p = 0.60). Body composition, lipid and glucose profiles, insulin sensitivity and adiponectin were likewise unaffected. Beta-cell function, as determined by the insulinogenic index (IGI), improved significantly (19.3 ± 13.7 vs 22.5 ± 17.6; p = 0.03; 16.5% increase from baseline in the telmisartan group). Conclusions. Telmisartan increased beta-cell function but did not decrease IMCL or liver fat content or other metabolic parameters among individuals with abdominal obesity.Trial registration: ClinicalTrials.gov identifier: NCT00147264.

Vascular endothelial growth factor-B as a therapeutic target to prevent ectopic fat deposition.

Vascular endothelial growth factor-B as a therapeutic target to prevent ectopic fat deposition.

Arsenic-Stimulated Lipolysis and Adipose Remodeling Is Mediated by G-Protein-Coupled Receptors

Arsenic in drinking water promotes a number of diseases that may stem from dysfunctional adipose lipid and glucose metabolism. Arsenic inhibits adipocyte differentiation and promotes insulin resistance; however, little is known of the impacts of and mechanisms for arsenic effects on adipose lipid storage and lipolysis. Based on our earlier studies of arsenic-signaling mechanisms for vascular remodeling and inhibition of adipogenesis, we investigated the hypothesis that arsenic acts through specific adipocyte G-protein-coupled receptors (GPCRs) to promote lipolysis and decrease lipid storage. We first demonstrated that 5-week exposure of mice to 100 μg/l of arsenic in drinking water stimulated epididymal adipocyte hypertrophy, reduced the adipose tissue expression of perilipin (PLIN1, a lipid droplet coat protein), and increased perivascular ectopic fat deposition in skeletal muscle. Incubating adipocytes, differentiated from adipose-derived human mesenchymal stem cell, with arsenic stimulated lipolysis and decreased both Nile Red positive lipid droplets and PLIN1 expression. Arsenic-stimulated lipolysis was not associated with increased cAMP levels. However, preincubation of adipocytes with the Gi inhibitor, Pertussis toxin, attenuated As(III)-stimulated lipolysis and lipid droplet loss. Antagonizing Gi-coupled endothelin-1 type A and B receptors (EDNRA/EDNRB) also attenuated arsenic effects, but antagonizing other adipose Gi-coupled receptors that regulate fat metabolism was ineffective. The endothelin receptors have different roles in arsenic responses because only EDNRA inhibition prevented arsenic-stimulated lipolysis, but antagonists to either receptor protected lipid droplets and PLIN1 expression. These data support a role for specific GPCRs in arsenic signaling for aberrant lipid storage and metabolism that may contribute to the pathogenesis of metabolic disease caused by environmental arsenic exposures.

Proliferation and Differentiation Potential of Adipose‐Derived Stem Cells Isolated from Dystrophin and Utrophin Double Knockout mice

Duchenne muscular dystrophy (DMD) is a genetic disease characterized by progressive weakening of the skeletal, cardiac, and diaphragmatic muscles. Recent evidence has emerged implicating adult stem cell dysfunction in DMD histophathogenesis. Using utrophin/dystrophin double knockout (dys−/−utro−/−, dKO) mice, a DMD model that better emulates the human phenotype of the disease in mice, we determine if adipose derived stem cells (ADSCs) from dKO mice are affected in their proliferation and differentiation capacities compared to C57BL (wt) ADSCs. ADSCs were isolated from subcutaneous fat tissue of 6 week old dKO and wt mice and flow analysis confirmed positive expressions of Sca‐1, CD34, CD44 and CD29. Cell proliferation assay using a Live Cell Imaging system showed that dKO‐ADSCs were more active in proliferation than wt‐ADSCs. dKO‐ADSCs showed increased adipogenic, osteogenic, and chondrogenic potentials compared to wt‐ADSCs in vitro. Additional experiments revealed that transplanted dKO‐ADSCs displayed increased proliferation and survival and formed/accumulated more adipocytes in dKO gastrocnemius muscle (GM) compared to that in wt GM. These results suggest that dystrophic muscle milieu affects the stem cell niche, impacting stem cell function to be more active in proliferation and adipogenesis and this may partially explain ectopic fat deposition in skeletal muscle seen in advanced cases of DMD.