Influence of muscle fiber type composition on early fat accumulation under high-fat diet challenge

Objective: To investigate whether differences in muscle fiber types affect early-stage fat accumulation, under high fat diet challenge in mice. Methods: Twelve healthy male C57BL/6 mice experienced with short-term (6 weeks) diet treatment for the evaluation of early pattern changes in muscular fat. The mice were randomly divided into two groups: high fat diet (n = 8) and normal control diet (n = 4). Extra- and intra-myocellular lipid (EMCL and IMCL) in lumbar muscles (type I fiber predominant) and tibialis anterior (TA) muscle (type II fiber predominant) were determined using magnetic resonance spectroscopy (MRS). Correlation of EMCL, IMCL and their ratio between TA and lumbar muscles was evaluated. Results: EMCL increased greatly in both muscle types after high fat diet. IMCL in TA and lumbar muscles increased to a much lower extent, with a slightly greater increase in TA muscles. EMCLs in the 2 muscles were positively correlated (r = 0.84, p = 0.01), but IMCLs showed a negative relationship (r = -0.84, p = 0.01). In lumbar muscles, high fat diet significantly decreased type I fiber while it increased type II fiber (all p≤0.001). In TA muscle, there was no significant fiber type shifting (p>0.05). Conclusions: Under short-time high fat diet challenge, lipid tends to initially accumulate extra-cellularly. In addition, compared to type II dominant muscle, Type I dominant muscle was less susceptible to IMCL accumulation but more to fiber type shifting. These phenomena might reflect compensative responses of skeletal muscle to dietary lipid overload in order to regulate metabolic homeostasis

Sulfatide-Hsp70 Interaction Promotes Hsp70 Clustering and Stabilizes Binding to Unfolded Protein

The 70-kDa heat shock protein (Hsp70), one of the major stress-inducible molecular chaperones, is localized not only in the cytosol, but also in extracellular milieu in mammals. Hsp70 interacts with various cell surface glycolipids including sulfatide (3'-sulfogalactosphingolipid). However, the molecular mechanism, as well as the biological relevance, underlying the glycolipid-Hsp70 interaction is unknown. Here we report that sulfatide promotes Hsp70 oligomerization through the N-terminal ATPase domain, which stabilizes the binding of Hsp70 to unfolded protein in vitro. We find that the Hsp70 oligomer has apparent molecular masses ranging from 440 kDa to greater than 669 kDa. The C-terminal peptide-binding domain is dispensable for the sulfatide-induced oligomer formation. The oligomer formation is impaired in the presence of ATP, while the Hsp70 oligomer, once formed, is unable to bind to ATP. These results suggest that sulfatide locks Hsp70 in a high-affinity state to unfolded proteins by clustering the peptide-binding domain and blocking the binding to ATP that induces the dissociation of Hsp70 from protein substrates

Glucagon-Like Peptide-1 Receptor Agonist Prevented the Progression of Hepatocellular Carcinoma in a Mouse Model of Nonalcoholic Steatohepatitis

Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat diabetes, but their effects on nonalcoholic steatohepatitis (NASH) and the development of hepatocellular carcinoma (HCC) remain unclear. In this study, mice with streptozotocin- and high-fat diet-induced diabetes and NASH were subcutaneously treated with liraglutide or saline (control) for 14 weeks. Glycemic control, hepatocarcinogenesis, and liver histology were compared between the groups. Fasting blood glucose levels were significantly lower in the liraglutide group than in the control group (210.0 ± 17.3 mg/dL vs. 601.8 ± 123.6 mg/dL), and fasting insulin levels were significantly increased by liraglutide (0.18 ± 0.06 ng/mL vs. 0.09 ± 0.03 ng/mL). Liraglutide completely suppressed hepatocarcinogenesis, whereas HCC was observed in all control mice (average tumor count, 5.5 ± 3.87; average tumor size, 8.1 ± 5.0 mm). Liraglutide significantly ameliorated steatosis, inflammation, and hepatocyte ballooning of non-tumorous lesions in the liver compared with the control findings, and insulin-positive β-cells were observed in the pancreas in liraglutide-treated mice but not in control mice. In conclusion, liraglutide ameliorated NASH and suppressed hepatocarcinogenesis in diabetic mice. GLP-1 receptor agonists can be used to improve the hepatic outcome of diabetes

Fiber type analysis of lumbar muscles.

<p>(<b>a</b>) Immunohistochemistry for type I and type II fiber in lumbar muscles. (<b>b</b>) Comparison of fiber type percentage in lumbar muscles between normal-control-diet (NCD) and high-fat-diet (HFD) mice. Type I fiber significantly decreased (p<0.001) and type II fiber significantly increased (p<0.001) in HFD mice (<b>C</b>) Correlation between intramyocellular lipid (IMCL) and percentage of type II fiber in lumbar muscle of HFD mice. IMCL positively correlates to percentage of type II fiber in HFD mice (r = 0.80, p = 0.03).</p

The comparison of tibialis anterior (TA) and lumbar muscles.

<p>Representative spectra of TA (a) and lumbar (b) muscles are shown. In both 1a and 1b, scout images (top row) indicate the location of voxels (purple boxes) in both the sagittal and axial view of leg or spinal muscles. Representative spectra (2^nd row, raw data) were presented for mice in both normal-control-diet (NCD, left) and high-fat-diet (HFD, right) groups; Raw spectra were analyzed in j-MRUI software to obtain individual fitted component (3^rd row, fitted data). The differences between raw data and fitted data in the 4^th row (residue); Cr, indicates creatine peak (3.02ppm), and used as reference to measure intramyocellular lipid (IMCL, (1.3ppm) and extramyocellular lipid (EMCL,1.5ppm). (c) The comparison of fat accumulation with and without HFD* Indicates p<0.05. The amount of IMCL/EMCL were recorded as a ratio to Cr-peak, hence it does not associate with an actual unit (y-axis). Representative histology (d) verifies the increases of EMCLs in both TA and lumbar muscles in HFD group. The pale spaces (indicated by “*”) between red stained cell marks the presences of EMCLs, whereas IMCL is not sensitive to the histological staining.</p