Lauren M Sparks

Sanford Burnham Prebys Medical Discovery Institute, لا هویا, California, United States

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Publications (33)210.41 Total impact

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    ABSTRACT: Disturbances in fatty acid metabolism may result in lipid accumulation in skeletal muscle (IMCL) and is associated with skeletal muscle insulin resistance (IR) and type 2 diabetes (T2D). Paradoxically, IMCL is increased in highly insulin sensitive endurance-trained athletes (ETAs), suggesting IMCL are not causative in IR. ETAs have a high capacity to oxidize IMCL, suggesting high IMCL turnover protects against IR. We investigated whether markers of IMCL turnover are elevated in ETAs.
    No preview · Article · Nov 2015
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    ABSTRACT: Exercise benefits most, but not all, individuals with type 2 diabetes mellitus (T2DM). The aim of this study was to determine whether a proportion of individuals with T2DM would fail to demonstrate exercise-induced metabolic improvements. We hypothesized that this lack of response would be related to their skeletal muscle transcriptional profile. 42 participants with T2DM from the previously reported HART-D study underwent a 9-month supervised exercise intervention. We performed a principal components analysis to distinguish Responders from Non-Responders (n=9 each) based on: decreases in (1) HbA1c, (2) %fat (3) BMI and (4) increase in skeletal muscle mtDNA. mRNA expression patterns in muscle tissue at baseline were assessed by microarray and qRT-PCR analysis in both groups. Of 186 genes identified by microarray analysis, 70% were up-regulated in Responders and down-regulated in Non-Responders. Several genes involved in substrate metabolism and mitochondrial biogenesis were significantly different (fold-change>1.5, p<0.05) between the groups at baseline, indicating a blunted oxidative capacity at baseline in Non-Responders. These data suggest that a unique baseline expression pattern of genes involved in muscle fuel metabolism may predict an individual's lack of exercise response in metabolic outcomes, thus allowing exercise interventions to be targeted to these individuals and aid in the identification of novel approaches to treat Non-Responders in the future. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jun 2015 · Metabolism: clinical and experimental
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    ABSTRACT: PGC1α, a transcriptional coactivator, interacts with PPARs and others to regulate skeletal muscle metabolism. PGC1α undergoes splicing to produce several mRNA variants, with the NTPGC1α variant having a similar biological function to the full length PGC1α (FLPGC1α). CVD is associated with obesity and T2D and a lower percentage of type 1 oxidative fibers and impaired mitochondrial function in skeletal muscle, characteristics determined by PGC1α expression. PGC1α expression is epigenetically regulated in skeletal muscle to determine mitochondrial adaptations, and epigenetic modifications may regulate mRNA splicing. We report in this paper that skeletal muscle PGC1α -1 nucleosome (-1N) position is associated with splice variant NTPGC1α but not FLPGC1α expression. Division of participants based on the -1N position revealed that those individuals with a -1N phased further upstream from the transcriptional start site (UP) expressed lower levels of NTPGC1α than those with the -1N more proximal to TSS (DN). UP showed an increase in body fat percentage and serum total and LDL cholesterol. These findings suggest that the -1N may be a potential epigenetic regulator of NTPGC1α splice variant expression, and -1N position and NTPGC1α variant expression in skeletal muscle are linked to CVD risk. This trial is registered with clinicaltrials.gov, identifier NCT00458133.
    Full-text · Article · Dec 2014 · PPAR Research
  • Natalie A Stephens · Lauren M Sparks
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    ABSTRACT: Context: Exercise benefits most, but not all, individuals with type 2 diabetes (T2D). The beneficial effects are well studied, but why some individuals do not respond favorably to exercise training is largely unexplored. It is critical to treatment and prevention strategies to identify individuals with T2D that have a blunted metabolic response to exercise and investigate the underlying mechanisms that might predict this "programmed response to fail." Evidence acquisition: We carried out a systematic review of classic and contemporary primary reports on clinical human and animal exercise studies. We also referenced unpublished data from our previous studies, as well those of collaborators. Genetic and epigenetic components and their associations with the exercise response were also examined. Evidence synthesis: As evidence of the exercise resistance premise, we and others found that supervised exercise training results in substantial response variations in glucose homeostasis, insulin sensitivity, and muscle mitochondrial density, wherein approximately 15-20% of individuals fail to improve their metabolic health with exercise. Classic genetic studies have shown that the extent of the exercise training response is largely heritable, whereas new evidence demonstrates that DNA hypomethylation is linked to the exercise response in skeletal muscle. DNA sequence variation and/or epigenetic modifications may, therefore, dictate the exercise training response. Conclusions: Studies dedicated to uncovering the mechanisms of exercise resistance will advance the field of exercise and T2D, allowing interventions to be targeted to those most likely to benefit and identify novel approaches to treat those who do not experience metabolic improvements after exercise training.
    No preview · Article · Nov 2014 · Journal of Clinical Endocrinology & Metabolism
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    ABSTRACT: Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide : NAD+ : precursors to increase oxidative phosphorylation and improve metabolic health, but human data is lacking. Here, we hypothesized that the nicotinic acid derivative Acipimox, a NAD(+) precursor, would directly affect mitochondrial function, independent of reductions in non-esterified fatty acid (NEFA) concentrations. In a multi-center randomized cross-over trial, 21 patients with type 2 diabetes (age 57.7±1.1 years, BMI, 33.4±0.8 kg/m(2)) received either placebo or 250 mg Acipimox thrice daily for 2 weeks. Acipimox treatment increased plasma NEFA (759±44 vs. 1135±97 µmol/L, p<0.01 for placebo vs. Acipimox), due to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that Acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene-sets and by presence of a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response (UPR(mt)). Further studies in C2C12 myotubes confirmed a direct effect of Acipimox on NAD+ levels, mitonuclear protein imbalance and mitochondrial oxidative capacity. To the best of our knowledge, this is the first demonstration that NAD+ boosters can also directly impact skeletal muscle mitochondrial function in humans.
    No preview · Article · Oct 2014 · Diabetes
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    ABSTRACT: Altered skeletal muscle lipid metabolism is a hallmark feature of type 2 diabetes (T2D). Here we investigated muscle lipid turnover in T2D versus BMI-matched controls and examined if putative in vivo differences would be preserved in the myotubes.Male obese T2D individuals (T2D) (n=6) and their BMI-matched controls (C) (n=6) underwent a hyperinsulinemic-euglycemic clamp, VO2max test, DXA scan, underwater weighing and muscle biopsy of v. lateralis. (14)C-palmitate and (14)C-oleate oxidation rates and incorporation into lipids were measured in muscle tissue, as well as in primary myotubes.Palmitate oxidation (C: 0.99 ± 0.17, T2D: 0.53 ± 0.07nmol/mg protein; P=0.03) and incorporation of fatty acids (FAs) into triacylglycerol (TAG) (C: 0.45 ± 0.13, T2D: 0.11 ± 0.02nmol/mg protein; P=0.047) were significantly reduced in muscle homogenates of T2D. These reductions were not retained for palmitate oxidation in primary myotubes (P=0.38); however, incorporation of FAs into TAG was lower in T2D (P=0.03 for oleate and P=0.11 for palmitate), with a strong correlation of TAG incorporation between muscle tissue and primary myotubes (r=0.848, P=0.008).Our data indicate that the ability to incorporate FAs into TAG is an intrinsic feature of human muscle cells that is reduced in individuals with T2D.
    Full-text · Article · Jan 2014 · Diabetes
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    ABSTRACT: To assess the determinants of exercise training-induced improvements in glucose control (HbA1C) including changes in serum total adiponectin and FFA concentrations, and skeletal muscle peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) protein content. A sub-cohort (n = 35; 48% men; 74% Caucasian) from the HART-D study undertaking muscle biopsies before and after 9 months of aerobic (AT), resistance (RT), or combination training (ATRT). Changes in HbA1C were associated with changes in adiponectin (r = -0.45, P = 0.007). Participants diagnosed with type 2 diabetes for a longer duration had the largest increase in PGC-1α (r = 0.44, P = 0.008). Statistical modeling examining changes in HbA1C suggested that male sex (P = 0.05), non-Caucasian ethnicity (P = 0.02), duration of type 2 diabetes (r = 0.40; P<0.002) and changes in FFA (r = 0.36; P<0.004), adiponectin (r = -0.26; P<0.03), and PGC-1α (r = -0.28; P = 0.02) explain ∼65% of the variability in the changes in HbA1C. Decreases in HbA1C after 9 months of exercise were associated with shorter duration of diabetes, lowering of serum FFA concentrations, increasing serum adiponectin concentrations and increasing skeletal muscle PGC-1α protein expression. ClinicalTrials.gov NCT00458133.
    Full-text · Article · Jun 2013 · PLoS ONE
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    ABSTRACT: Context:Since the discovery of functional brown adipose tissue (BAT) in adult humans, there has been a renewed interest in the physiology of human BAT. Imaging studies from our laboratory and others have shown increased glucose uptake in adipose tissue regions assumed to be BAT in humans. We have also shown that human BAT from the supraclavicular (SCV) region is positive for uncoupling protein-1. To date, however, the oxidative capacity of this adipose tissue (AT) depot has not been characterized in humans.Objective:We hypothesize that oxidative capacity is increased in the AT of the SCV region known to contain human BAT.Design:This was an observational prospective cohort study.Setting:The study was conducted at a referral center.Patients:Participants were 13 patients for whom thyroid gland surgery was indicated.Main Outcome Measure:Basal cellular oxygen consumption in human AT biopsy samples from the SCV region, known to be [(18)F]fluorodeoxyglucose positron emission tomography-computed tomography-positive, was compared with the cellular oxygen consumption in subcutaneous white adipose tissue (WAT) from the same region of the same subject.Results:We show for the first time that AT from the human BAT region displays increased oxygen consumption (P < .05), on average 300% higher, than subcutaneous WAT of the same individual. The contribution of the proton leak to maximal respiration increased with age in the WAT but not in the AT from the BAT region.Conclusions:These results suggest that human adipose tissue from the BAT region can be distinguished from subcutaneous WAT by a higher basal oxidative capacity. Additional studies are warranted to further elucidate the metabolic and bioenergetic characteristics of this AT depot in humans.
    No preview · Article · Jun 2013 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: Context:Type 2 diabetes (T2D) has features of disordered lipid and glucose metabolism, due in part to reduced mitochondrial content.Objective:Our objective was to investigate effects of different types of exercise on mitochondrial content and substrate oxidation in individuals with T2D (ancillary study of the randomized controlled trial Health Benefits of Aerobic and Resistance Training in Individuals with Type 2 Diabetes, HART-D).Intervention:T2D individuals were randomized to aerobic training (AT, n = 12), resistance training (RT, n = 18), combination training (ATRT, n = 12), or nonexercise control (n = 10). Blood draws, peak oxygen consumption tests, dual-energy x-ray absorptiometry scans and muscle biopsies of vastus lateralis were performed before and after 9 months. Ex vivo substrate oxidations (14CO2), mitochondrial content, and enzyme activities were measured. Glycated hemoglobin A1c and free fatty acids were also determined.Results:Mitochondrial content increased after RT and ATRT. Octanoate oxidation increased after AT and ATRT, whereas palmitate, pyruvate, and acetate oxidations increased in all exercise groups. Exercise-induced responses in mitochondrial DNA were associated with improvements in peak oxygen consumption, β-hydroxyacyl-coenzyme A dehydrogenase activity, and palmitate oxidation.Conclusions:Nine months of AT and RT significantly improved most aspects of skeletal muscle mitochondrial content and substrate oxidation, whereas the combination improved all aspects. These exercise responses were associated with clinical improvements, indicating that long-term training, especially combination, is an effective lifestyle therapy for individuals with T2D by way of improving muscle substrate metabolism.
    No preview · Article · Mar 2013 · The Journal of Clinical Endocrinology and Metabolism
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    Preview · Article · Mar 2013 · Circulation Research
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    ABSTRACT: Mitochondrial dysfunction, lipid accumulation, insulin resistance and metabolic inflexibility have been implicated in the etiology of type 2 diabetes (T2D), yet their interrelationship remains speculative. We investigated these interrelationships in a group of T2D and obese normoglycemic control subjects. 49 non-insulin dependent male T2D patients and 54 male control subjects were enrolled, and a hyperinsulinemic-euglycemic clamp and indirect calorimetry were performed. A muscle biopsy was taken and intramyocellular lipid (IMCL) was measured. In vivo mitochondrial function was measured by PCr recovery in 30 T2D patients and 31 control subjects. Fasting NEFA levels were significantly elevated in T2D patients compared with controls, but IMCL was not different. Mitochondrial function in T2D patients was compromised by 12.5% (p<0.01). Whole body glucose disposal (WGD) was higher at baseline and lower after insulin stimulation. Metabolic flexibility (ΔRER) was lower in the type 2 diabetic patients (0.050±0.033 vs. 0.093±0.050, p<0.01). Mitochondrial function was the sole predictor of basal respiratory exchange ratio (RER) (R(2) = 0.18, p<0.05); whereas WGD predicted both insulin-stimulated RER (R(2) = 0.29, p<0.001) and metabolic flexibility (R(2) = 0.40, p<0.001). These results indicate that defects in skeletal muscle in vivo mitochondrial function in type 2 diabetic patients are only reflected in basal substrate oxidation and highlight the importance of glucose disposal rate as a determinant of substrate utilization in response to insulin.
    Full-text · Article · Feb 2013 · PLoS ONE
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    ABSTRACT: Aims/hypothesis: While lipid deposition in the skeletal muscle is considered to be involved in obesity-associated insulin resistance, neutral intramyocellular lipid (IMCL) accumulation per se does not necessarily induce insulin resistance. We previously demonstrated that overexpression of the lipid droplet coat protein perilipin 2 augments intramyocellular lipid content while improving insulin sensitivity. Another member of the perilipin family, perilipin 5 (PLIN5), is predominantly expressed in oxidative tissues like the skeletal muscle. Here we investigated the effects of PLIN5 overexpression - in comparison with the effects of PLIN2 - on skeletal muscle lipid levels, gene expression profiles and insulin sensitivity. Methods: Gene electroporation was used to overexpress PLIN5 in tibialis anterior muscle of rats fed a high fat diet. Eight days after electroporation, insulin-mediated glucose uptake in the skeletal muscle was measured by means of a hyperinsulinemic euglycemic clamp. Electron microscopy, fluorescence microscopy and lipid extractions were performed to investigate IMCL accumulation. Gene expression profiles were obtained using microarrays. Results: TAG storage and lipid droplet size increased upon PLIN5 overexpression. Despite the higher IMCL content, insulin sensitivity was not impaired and DAG and acylcarnitine levels were unaffected. In contrast to the effects of PLIN2 overexpression, microarray data analysis revealed a gene expression profile favoring FA oxidation and improved mitochondrial function. Conclusions/interpretation: Both PLIN2 and PLIN5 increase neutral IMCL content without impeding insulin-mediated glucose uptake. As opposed to the effects of PLIN2 overexpression, overexpression of PLIN5 in the skeletal muscle promoted expression of a cluster of genes under control of PPARα and PGC1α involved in FA catabolism and mitochondrial oxidation.
    Full-text · Article · Jan 2013 · Biochimica et Biophysica Acta
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    ABSTRACT: Intramuscular accumulation of triacylglycerol, in the form of lipid droplets (LD), has gained widespread attention as a hallmark of metabolic disease and insulin resistance. Paradoxically, LDs also amass in muscles of highly trained endurance athletes that are exquisitely insulin sensitive. Understanding the molecular mechanisms that mediate the expansion and appropriate metabolic control of LDs in the context of habitual physical activity could lead to new therapeutic opportunities. Herein, we show that acute exercise elicits robust upregulation of a broad program of genes involved in regulating LD assembly, morphology, localization and mobilization. Prominent among these was perilipin-5, a scaffolding protein that affects the spatial and metabolic interactions between LD and their surrounding mitochondrial reticulum. Studies in transgenic mice and primary human skeletal myocytes established a key role for the exercise-responsive transcriptional co-activator, PGC-1α, in coordinating intramuscular LD programming with mitochondrial remodeling. Moreover, translational studies comparing physically active versus inactive humans identified a remarkably strong association between expression of intramuscular LD genes and enhanced insulin action in exercise trained subjects. These results reveal an intimate molecular connection between intramuscular LD biology and mitochondrial metabolism that could prove relevant to the etiology and treatment of insulin resistance other disorders of lipid imbalance.
    Full-text · Article · Nov 2012 · The Journal of Lipid Research
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    ABSTRACT: Type 2 diabetes is characterized by excessive lipid storage in skeletal muscle. Excessive intramyocellular lipid (IMCL) storage exceeds intracellular needs and induces lipotoxic events, ultimately contributing to the development of insulin resistance. Lipid droplet (LD)-coating proteins may control proper lipid storage in skeletal muscle. Perilipin 2 (PLIN2/adipose differentiation-related protein [ADRP]) is one of the most abundantly expressed LD-coating proteins in skeletal muscle. Here we examined the role of PLIN2 in myocellular lipid handling and insulin sensitivity by investigating the effects of in vitro PLIN2 knockdown and in vitro and in vivo overexpression. PLIN2 knockdown decreased LD formation and triacylglycerol (TAG) storage, marginally increased fatty-acid (FA) oxidation, and increased incorporation of palmitate into diacylglycerols and phospholipids. PLIN2 overexpression in vitro increased intramyocellular TAG storage paralleled with improved insulin sensitivity. In vivo muscle-specific PLIN2 overexpression resulted in increased LD accumulation and blunted the high-fat diet-induced increase in protein content of the subunits of the oxidative phosphorylation (OXPHOS) chain. Diacylglycerol levels were unchanged, whereas ceramide levels were increased. Despite the increased IMCL accumulation, PLIN2 overexpression improved skeletal muscle insulin sensitivity. We conclude that PLIN2 is essential for lipid storage in skeletal muscle by enhancing the partitioning of excess FAs toward TAG storage in LDs, thereby blunting lipotoxicity-associated insulin resistance.
    Full-text · Article · Jul 2012 · Diabetes
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    ABSTRACT: Brown fat generates heat via the mitochondrial uncoupling protein UCP1, defending against hypothermia and obesity. Recent data suggest that there are two distinct types of brown fat: classical brown fat derived from a myf-5 cellular lineage and UCP1-positive cells that emerge in white fat from a non-myf-5 lineage. Here, we report the isolation of "beige" cells from murine white fat depots. Beige cells resemble white fat cells in having extremely low basal expression of UCP1, but, like classical brown fat, they respond to cyclic AMP stimulation with high UCP1 expression and respiration rates. Beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin. Finally, we provide evidence that previously identified brown fat deposits in adult humans are composed of beige adipocytes. These data provide a foundation for studying this mammalian cell type with therapeutic potential. PAPERCLIP:
    Full-text · Article · Jul 2012 · Cell
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    ABSTRACT: Fat accumulation in skeletal muscle combined with low mitochondrial oxidative capacity is associated with insulin resistance (IR). Endurance-trained athletes, characterized by a high oxidative capacity, have elevated intramyocellular lipids, yet are highly insulin sensitive. We tested the hypothesis that a high oxidative capacity could attenuate lipid-induced IR. Nine endurance-trained (age = 23.4 ± 0.9 years; BMI = 21.2 ± 0.6 kg/m(2)) and 10 untrained subjects (age = 21.9 ± 0.9 years; BMI = 22.8 ± 0.6 kg/m(2)) were included and underwent a clamp with either infusion of glycerol or intralipid. Muscle biopsies were taken to perform high-resolution respirometry and protein phosphorylation/expression. Trained subjects had ∼32% higher mitochondrial capacity and ∼22% higher insulin sensitivity (P < 0.05 for both). Lipid infusion reduced insulin-stimulated glucose uptake by 63% in untrained subjects (P < 0.05), whereas this effect was blunted in trained subjects (29%, P < 0.05). In untrained subjects, lipid infusion reduced oxidative and nonoxidative glucose disposal (NOGD), whereas trained subjects were completely protected against lipid-induced reduction in NOGD, supported by dephosphorylation of glycogen synthase. We conclude that chronic exercise training attenuates lipid-induced IR and specifically attenuates the lipid-induced reduction in NOGD. Signaling data support the notion that high glucose uptake in trained subjects is maintained by shuttling glucose toward storage as glycogen.
    Full-text · Article · Jul 2012 · Diabetes
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    ABSTRACT: Insulin resistance is characterized by disturbances in lipid metabolism in skeletal muscle. Our aim was to investigate whether gene expression and fatty acid (FA) profile of skeletal muscle lipids are affected by diets differing in fat quantity and quality in subjects with the metabolic syndrome (MetS) and varying degrees of insulin sensitivity. 84 subjects (age 57.3±0.9 y, BMI 30.9±0.4kg/m(2), 42M/42F) were randomly assigned to one of four iso-energetic diets: high-SFA (HSFA); high-MUFA (HMUFA) or two low-fat, high-complex carbohydrate diets, supplemented with 1.24g/day of long-chain n-3 PUFA (LFHCCn-3) or control oil (LFHCC) for 12weeks. In a subgroup of men (n=26), muscle TAG, DAG, FFA and phospholipid contents were determined including their fractional synthetic rate (FSR) and FA composition at fasting and 4h after consumption of a high-fat mixed-meal, both pre- and post-intervention. Genes involved in lipogenesis were downregulated after HMUFA (mean fold change -1.3) and after LFHCCn-3 (fold change -1.7) in insulin resistant subjects (< median of (S(I))), whereas in insulin sensitive subjects (>median of insulin sensitivity) the opposite effect was shown (fold change +1.6 for both diets). HMUFA diet tended to decrease FSR in TAG (P=.055) and DAG (P=.066), whereas the LFHCCn-3 diet reduced TAG content (P=.032). In conclusion, HMUFA and LFHCCn-3 diets reduced the expression of the lipogenic genes in skeletal muscle of insulin resistant subjects, whilst HMUFA reduced the fractional synthesis rate of DAG and TAG and LFHCC n-3 the TAG content. Our data indicate that these diets may reduce muscle fat accumulation by affecting the balance between FA synthesis, storage and oxidation.
    No preview · Article · Jun 2012 · Metabolism: clinical and experimental
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    ABSTRACT: In addition to adipose tissue, recent studies suggest that skeletal muscle may also be a source of low-grade inflammation, particularly in inactive and/or overweight individuals. The aim of this study was to examine the presence of macrophages in skeletal muscle from obese subjects with type 2 diabetes (T2D) before and after a 9-month exercise program (vs. a non-exercising control group) (Study 1) and in young vs. elderly subjects (Study 2). In both studies, CD68(+) macrophages in vastus lateralis biopsies were determined by immunohistochemistry and inflammation gene expression measured. Macrophage content (%) was calculated by the number of macrophages per 100 muscle fibers. In Study 1, we found relatively low numbers (2-3%) of CD68(+) macrophages in skeletal muscle in obese T2D subjects (BMI = 37.3 ± 5.2 kg/m(2)), which were unchanged after a 9-month exercise program (P = 0.42). Similarly, in Study 2 (BMI = 27.1 ± 2.5 kg/m(2)), CD68(+) macrophages were relatively low in muscle (4-5%) and were not different between young and elderly individuals (P = 0.42). However, elderly subjects had twofold higher CD68 and CD206 gene expression (both P < 0.002) than young participants. In both studies, CD68(+) muscle macrophages were not associated with BMI. In conclusion, we found little evidence of macrophage accumulation in skeletal muscle in obese T2D subjects or in elderly individuals. A 9-month exercise program was not associated with a decrease in macrophage content.
    Full-text · Article · Feb 2012 · Obesity
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    ABSTRACT: Perilipin 5 (PLIN5/OXPAT) is a lipid droplet (LD) coat protein mainly present in tissues with a high fat-oxidative capacity, suggesting a role for PLIN5 in facilitating fatty acid oxidation. Here, we investigated the role of PLIN5 in fat oxidation in skeletal muscle. In human skeletal muscle, we observed that PLIN5 (but not PLIN2) protein content correlated tightly with OXPHOS content and in rat muscle PLIN5 content correlated with mitochondrial respiration rates on a lipid-derived substrate. This prompted us to examine PLIN5 protein expression in skeletal muscle mitochondria by means of immunogold electron microscopy and Western blots in isolated mitochondria. These data show that PLIN5, in contrast to PLIN2, not only localizes to LD but also to mitochondria, possibly facilitating fatty acid oxidation. Unilateral overexpression of PLIN5 in rat anterior tibialis muscle augmented myocellular fat storage without increasing mitochondrial density as indicated by the lack of change in protein content of five components of the OXPHOS system. Mitochondria isolated from PLIN5 overexpressing muscles did not possess increased fatty acid respiration. Interestingly though, (14)C-palmitate oxidation assays in muscle homogenates from PLIN5 overexpressing muscles revealed a 44.8% (P = 0.05) increase in complete fatty acid oxidation. Thus, in mitochondrial isolations devoid of LD, PLIN5 does not augment fat oxidation, while in homogenates containing PLIN5-coated LD, fat oxidation is higher upon PLIN5 overexpression. The presence of PLIN5 in mitochondria helps to understand why PLIN5, in contrast to PLIN2, is of specific importance in fat oxidative tissues. Our data suggests involvement of PLIN5 in directing fatty acids from the LD to mitochondrial fatty acid oxidation.
    Full-text · Article · Nov 2011 · Histochemie
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    ABSTRACT: Disturbances in lipid metabolism are strongly associated with insulin resistance and type 2 diabetes (T2D). We hypothesized that activation of cAMP/PKA and calcium signaling pathways in cultured human myotubes would provide further insight into regulation of lipid storage, lipolysis, lipid oxidation and insulin responsiveness. Human myoblasts were isolated from vastus lateralis, purified, cultured and differentiated into myotubes. All cells were incubated with palmitate during differentiation. Treatment cells were pulsed 1 hour each day with forskolin and ionomycin (PFI) during the final 3 days of differentiation to activate the cAMP/PKA and calcium signaling pathways. Control cells were not pulsed (control). Mitochondrial content, (14)C lipid oxidation and storage were measured, as well as lipolysis and insulin-stimulated glycogen storage. Myotubes were stained for lipids and gene expression measured. PFI increased oxidation of oleate and palmitate to CO(2) (p<0.001), isoproterenol-stimulated lipolysis (p = 0.01), triacylglycerol (TAG) storage (p<0.05) and mitochondrial DNA copy number (p = 0.01) and related enzyme activities. Candidate gene and microarray analysis revealed increased expression of genes involved in lipolysis, TAG synthesis and mitochondrial biogenesis. PFI increased the organization of lipid droplets along the myofibrillar apparatus. These changes in lipid metabolism were associated with an increase in insulin-mediated glycogen storage (p<0.001). Activation of cAMP/PKA and calcium signaling pathways in myotubes induces a remodeling of lipid droplets and functional changes in lipid metabolism. These results provide a novel pharmacological approach to promote lipid metabolism and improve insulin responsiveness in myotubes, which may be of therapeutic importance for obesity and type 2 diabetes.
    Full-text · Article · Jul 2011 · PLoS ONE

Publication Stats

2k Citations
210.41 Total Impact Points

Institutions

  • 2014-2015
    • Sanford Burnham Prebys Medical Discovery Institute
      • Diabetes and Obesity Research Center
      لا هویا, California, United States
  • 2012-2014
    • Maastricht Universitair Medisch Centrum
      • Central Diagnostic Laboratory
      Maestricht, Limburg, Netherlands
  • 2010-2014
    • Maastricht University
      • NUTRIM School for Nutrition, Toxicology and Metabolism
      Maestricht, Limburg, Netherlands
  • 2013
    • Louisiana State University
      • Pennington Biomedical Research Center
      Baton Rouge, Louisiana, United States
  • 2005-2012
    • Pennington Biomedical Research Center
      Baton Rouge, Louisiana, United States
  • 2008
    • University of California, Los Angeles
      • Department of Human Genetics
      Los Angeles, California, United States
  • 2006
    • Louisiana State University Agricultural Center
      Baton Rouge, Louisiana, United States