Exercise training results in depot-specific adaptations to adipose tissue mitochondrial function

We assessed differences in mitochondrial function in gluteal (gSAT) and abdominal subcutaneous adipose tissue (aSAT) at baseline and in response to 12-weeks of exercise training; and examined depot-specific associations with body fat distribution and insulin sensitivity (S-I). Obese, black South African women (n = 45) were randomized into exercise (n = 23) or control (n = 22) groups. Exercise group completed 12-weeks of aerobic and resistance training (n = 20), while the control group (n = 15) continued usual behaviours. Mitochondrial function (high-resolution respirometry and fluorometry) in gSAT and aSAT, SI (frequently sampled intravenous glucose tolerance test), body composition (dual-energy X-ray absorptiometry), and ectopic fat (MRI) were assessed pre- and post-intervention. At baseline, gSAT had higher mitochondrial respiratory capacity and hydrogen peroxide (H2O2) production than aSAT (p < 0.05). Higher gSAT respiration was associated with higher gynoid fat (p < 0.05). Higher gSAT H2O2 production and lower aSAT mitochondrial respiration were independently associated with lower SI (p < 0.05). In response to training, S-I improved and gynoid fat decreased (p < 0.05), while H2O2 production reduced in both depots, and mtDNA decreased in gSAT (p < 0.05). Mitochondrial respiration increased in aSAT and correlated with a decrease in body fat and an increase in soleus and hepatic fat content (p < 0.05). This study highlights the importance of understanding the differences in mitochondrial function in multiple SAT depots when investigating the pathophysiology of insulin resistance and associated risk factors such as body fat distribution and ectopic lipid deposition. Furthermore, we highlight the benefits of exercise training in stimulating positive adaptations in mitochondrial function in gluteal and abdominal SAT depots

Proton Nuclear Magnetic Resonance Investigation of the Mechanism of the Reconstitution of Myoglobin That Leads to Metastable Heme Orientational Disorder

The nature of the initially formed complexes between sperm whale apomyoglobin and hemin has been investigated by 1H NMR for the purpose of elucidating the factors that give rise to heme orientational disorder in the reconstitution process. Selective removal of each of the two propionate side chains leads to an initial complex upon reconstitution (in the presence of a non-interacting organic solvent) with strong selectivity for the heme orientation which places the sole propionate into the position occupied by the 6-propionate group in the crystal structure. Hence the propionate contacts with apomyoglobin lead to the heme disorder about the α,γ-meso axis. Equilibration yields a unique heme orientation identical to that found in native Mb single crystals. Reconstitution of apomyoglobin with iron-free protoporphyrin yields only a single heme orientation within the time needed to obtain a NMR spectrum. However, this is concluded to result from rapid equilibration rather than from unique insertion of the porphyrin. The larger ring current for the des-iron myoglobin complex is interpreted in terms of protonation of the His F8 side chain that interacts with the porphyrin core. Pyridine is shown to interact strongly with cyanomet myoglobin, and the induced changes in hyperfine shifts show a spatial selectivity which suggests that pyridine intercalates on the proximal side of the heme. © 1989, American Chemical Society. All rights reserved

Improved peripheral and hepatic insulin sensitivity after lifestyle interventions in type 2 diabetes is associated with specific metabolomic and lipidomic signatures in skeletal muscle and plasma

Lifestyle interventions with weight loss can improve insulin sensitivity in type 2 diabetes (T2D), but mechanisms are unclear. We explored circulating and skeletal muscle metabolite signatures of altered peripheral (pIS) and hepatic insulin sensitivity (hIS) in overweight and obese T2D individuals that were randomly assigned a 12-week Paleolithic-type diet with (diet-ex, n = 13) or without (diet, n = 13) supervised exercise. Baseline and post-intervention measures included: mass spectrometry-based metabolomics and lipidomics of skeletal muscle and plasma; pIS and hIS; ectopic lipid deposits in the liver and skeletal muscle; and skeletal muscle fat oxidation rate. Both groups lowered BMI and total % fat mass and increased their pIS. Only the diet-group improved hIS and reduced ectopic lipids in the liver and muscle. The combined improvement in pIS and hIS in the diet-group were associated with decreases in muscle and circulating branched-chain amino acid (BCAA) metabolites, specifically valine. Improved pIS with diet-ex was instead linked to increased diacylglycerol (34:2) and triacylglycerol (56:0) and decreased phosphatidylcholine (34:3) in muscle coupled with improved muscle fat oxidation rate. This suggests a tissue crosstalk involving BCAA-metabolites after diet intervention with improved pIS and hIS, reflecting reduced lipid influx. Increased skeletal muscle lipid utilization with exercise may prevent specific lipid accumulation at sites that perturb insulin signaling

Exercise Training Adds Cardiometabolic Benefits of a Paleolithic Diet in Type 2 Diabetes Mellitus

Background: The accumulation of myocardial triglycerides and remodeling of the left ventricle are common features in type 2 diabetes mellitus and represent potential risk factors for the development of diastolic and systolic dysfunction. A few studies have investigated the separate effects of diet and exercise training on cardiac function, but none have investigated myocardial changes in response to a combined diet and exercise intervention. This 12-week randomized study assessed the effects of a Paleolithic diet, with and without additional supervised exercise training, on cardiac fat, structure, and function. Methods and Results: Twenty-two overweight and obese subjects with type 2 diabetes mellitus were randomized to either a Paleolithic diet and standard-care exercise recommendations ( PD ) or to a Paleolithic diet plus supervised exercise training 3 hours per week ( PD - EX ). This study includes secondary end points related to cardiac structure and function, ie, myocardial triglycerides levels, cardiac morphology, and strain were measured using cardiovascular magnetic resonance, including proton spectroscopy, at baseline and after 12 weeks. Both groups showed major favorable metabolic changes. The PD - EX group showed significant decreases in myocardial triglycerides levels (-45%, P=0.038) and left ventricle mass to end-diastolic volume ratio (-13%, P=0.008) while the left ventricle end-diastolic volume and stroke volume increased significantly (+14%, P=0.004 and +17%, P=0.008, respectively). These variables were unchanged in the PD group. Conclusions: Exercise training plus a Paleolithic diet reduced myocardial triglycerides levels and improved left ventricle remodeling in overweight/obese subjects with type 2 diabetes mellitus. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01513798

\u3csup\u3e1\u3c/sup\u3eH NMR investigation of the role of intrinsic heme versus protein- induced rhombic perturbations on the electronic structure of low-spin ferrihemoproteins: Effect of heme substituents on heme orientation in myoglobin

Solution 1H NMR spectroscopy has been used to characterize the cyanomet myoglobin complexes of a variety of chemically modified hemins in order to elucidate the importance of hemin peripheral electronic, relative to axial his imidazole-induced, rhombic perturbations in raising the orbital degeneracy of the π-bonding d(xz),d(yz) orbitals. Variation of the hemin 2- and/or 4-position substituents among hydrogen, ethyl, vinyl, acetyl, and formyl groups leads to conserved molecular structure of the heme pocket and orientation of the major magnetic axis for the heme iron, but systematically perturbed heme methyl contact shift patterns. Two strongly rhombically perturbed hemins with single acetyl groups on either pyrrole I or II exhibit heme methyl contact shift patterns and characteristic deviations from Curie law that are very similar to that induced in pseudosymmetric hemins upon incorporation into metMbCN in the alternate orientations about the α,γ- meso axis. The perturbation due to the 4-acetyl group and the axial his bond leads to increased contact shift spread and stronger deviations from Curie behavior compared to WT, indicative of an increased d(xz)/d(yz) spacing relative to WT. In contrast, the perturbation due to the 2-acetyl group and axial his nearly cancel, leading to a highly compressed methyl contact shift spread and weaker deviations from Curie behavior than WT. It is shown, moreover, that the larger d(xz)/d(yz) splitting with 4-acetylhemin, and the smaller splitting with 2-acetylhemin, relative to WT, result in the expected increase and decrease, respectively, for the axial his contact shift relative to WT. Comparison of the methyl shifts for 16 peripherally modified hemins as model compounds and incorporated into metMbCN shows that the rhombic influences are additive in each of the complexes. Thus, the present results show that chemical functionality of the heme periphery contributes to raising the orbital degeneracy of the heme iron and that such influences can account for orbital ground States that are not necessarily aligned with the axial his orientation. The range of variant 2- and/or 4-substitutions have led to equilibrium heme orientations that are largely the same as found in WT Mb, except for a 4-ethyl group, which favors the reversed heme orientation by 2:1

Liquefaction caused by the 2009 Olancha, California (USA), M5.2 earthquake

The October 3, 2009 (01:16:00 UTC), Olancha M5.2 earthquake caused extensive liquefaction as well as permanent horizontal ground deformation within a 1.2 km^2 area earthquake in Owens Valley in eastern California (USA). Such liquefaction is rarely observed during earthquakes of M ≤ 5.2. We conclude that subsurface conditions, not unusual ground motion, were the primary factors contributing to the liquefaction. The liquefaction occurred in very liquefiable sands at shallow depth (< 2 m) in an area where the water table was near the land surface. Our investigation is relevant to both geotechnical engineering and geology. The standard engineering method for assessing liquefaction potential, the Seed–Idriss simplified procedure, successfully predicted the liquefaction despite the small earthquake magnitude. The field observations of liquefaction effects highlight a need for caution by earthquake geologists when inferring prehistoric earthquake magnitudes from paleoliquefaction features because small magnitude events may cause such features

Exercise training improves mitochondrial respiration and is associated with an altered intramuscular phospholipid signature in women with obesity

Aims/hypothesis: We sought to determine putative relationships among improved mitochondrial respiration, insulin sensitivity and altered skeletal muscle lipids and metabolite signature in response to combined aerobic and resistance training in women with obesity. Methods: This study reports a secondary analysis of a randomised controlled trial including additional measures of mitochondrial respiration, skeletal muscle lipidomics, metabolomics and protein content. Women with obesity were randomised into 12 weeks of combined aerobic and resistance exercise training (n = 20) or control (n = 15) groups. Pre- and post-intervention testing included peak oxygen consumption, whole-body insulin sensitivity (intravenous glucose tolerance test), skeletal muscle mitochondrial respiration (high-resolution respirometry), lipidomics and metabolomics (mass spectrometry) and lipid content (magnetic resonance imaging and spectroscopy). Proteins involved in glucose transport (i.e. GLUT4) and lipid turnover (i.e. sphingomyelin synthase 1 and 2) were assessed by western blotting. Results: The original randomised controlled trial showed that exercise training increased insulin sensitivity (median [IQR]; 3.4 [2.0–4.6] to 3.6 [2.4–6.2] x10−5 pmol l−1 min−1), peak oxygen consumption (mean ± SD; 24.9 ± 2.4 to 27.6 ± 3.4 ml kg−1 min−1), and decreased body weight (84.1 ± 8.7 to 83.3 ± 9.7 kg), with an increase in weight (pre intervention, 87.8± 10.9 to post intervention 88.8 ± 11.0 kg) in the control group (interaction p &lt; 0.05). The current study shows an increase in mitochondrial respiration and content in response to exercise training (interaction p &lt; 0.05). The metabolite and lipid signature at baseline were significantly associated with mitochondrial respiratory capacity (p &lt; 0.05) but were not associated with whole-body insulin sensitivity or GLUT4 protein content. Exercise training significantly altered the skeletal muscle lipid profile, increasing specific diacylglycerol(32:2) and ceramide(d18:1/24:0) levels, without changes in other intermediates or total content of diacylglycerol and ceramide. The total content of cardiolipin, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) increased with exercise training with a decrease in the PC:PE ratios containing 22:5 and 20:4 fatty acids. These changes were associated with content-driven increases in mitochondrial respiration (p &lt; 0.05), but not with the increase in whole-body insulin sensitivity or GLUT4 protein content. Exercise training increased sphingomyelin synthase 1 (p &lt; 0.05), with no change in plasma-membrane-located sphingomyelin synthase 2. Conclusions/interpretation: The major findings of our study were that exercise training altered specific intramuscular lipid intermediates, associated with content-driven increases in mitochondrial respiration but not whole-body insulin sensitivity. This highlights the benefits of exercise training and presents putative target pathways for preventing lipotoxicity in skeletal muscle, which is typically associated with the development of type 2 diabetes

β-cell function in black South African women:exploratory associations with insulin clearance, visceral and ectopic fat

The role of ectopic fat, insulin secretion and clearance in the preservation of β-cell function in black African women with obesity who typically present with hyperinsulinaemia is not clear. We aim to examine the associations between disposition index (DI, an estimate of β-cell function), insulin secretion and clearance and ectopic fat deposition. This is a cross-sectional study of 43 black South African women (age 20–35 years) with obesity (BMI 30–40 kg/m2) and without type 2 diabetes that measured the following: DI, insulin sensitivity (SI), acute insulin response (AIRg), insulin secretion rate (ISR), hepatic insulin extraction and peripheral insulin clearance (frequently sampled i.v. glucose tolerance test); pancreatic and hepatic fat, visceral adipose tissue (VAT) and abdominal s.c. adipose tissue (aSAT) volume (MRI), intra-myocellular (IMCL) and extra-myocellular fat content (EMCL) (magnetic resonance spectroscopy). DI correlated positively with peripheral insulin clearance (β 55.80, P = 0.002). Higher DI was associated with lower VAT, pancreatic fat and soleus fat, but VAT explained most of the variance in DI (32%). Additionally, higher first phase ISR (P = 0.033) and lower hepatic insulin extraction (P = 0.022) were associated with lower VAT, independent from SI, rather than with ectopic fat. In conclusion, peripheral insulin clearance emerged as an important correlate of DI. However, VAT was the main determinant of a lower DI above ectopic fat depots. Importantly, VAT, but not ectopic fat, is associated with both lower insulin secretion and higher hepatic insulin extraction. Prevention of VAT accumulation in young black African women should, therefore, be an important target for beta cell preservation