Savage, D. B. | bioRxiv Science

bioRxiv2018

Magnetic resonance spectroscopy analysis of intramyocellular lipid composition in lipodystrophic patients and athletes

ContextParadoxically, intramyocellular lipid (IMCL) accumulation has been linked to both insulin-resistant and to insulin-sensitive (athletes) states. The composition of this lipid store is unknown in these states.\n\nDesign and MethodsWe used a recently validated and potentially widely applicable 1H magnetic resonance spectroscopy method to compare the compositional saturation index (CH2:CH3 ratio) and concentration independent of composition (CH3) of intramyocellular lipid in the soleus and tibialis anterior muscles of 16 female insulin-resistant lipodystrophic patients with that of age- and gender-matched athletes (n=14) and healthy controls (n = 41).\n\nMain OutcomeIMCL compositional saturation index (CH2:CH3 ratio).\n\nResultsThe IMCL CH2:CH3 ratio was significantly higher in both muscles of the lipodystrophic patients compared with age- and gender-matched controls but not compared to athletes. IMCL CH2:CH3 was dependent on IMCL concentration in the controls and after adjusting the composition index for quantity (CH2:CH3adj) was able to distinguish patients from athletes. With groups pooled, this CH2:CH3adj marker had the strongest relation to insulin resistance (HOMA-IR) compared to other measures of lipid concentration and composition, especially in the soleus muscle. Contrary to the athletes paradox, IMCL in athletes was similar in tibialis anterior (p>0.05) and significantly lower in the soleus (p < 0.004) compared to both controls and patients.\n\nConclusionsThe IMCL saturation index adjusted for quantity, which likely reflects accumulation of saturated IMCL, is more closely associated with insulin resistance than concentration alone.

biochemistry↗

bioRxiv2018

Genome-wide scan and fine-mapping of rare nonsynonymous associations implicates intracellular lipolysis genes in fat distribution and cardio-metabolic risk

Difficulties in identifying causal variants and genes underlying genetic associations have limited the translational potential of genetic studies of body fat distribution, an important, partly-heritable risk factor for cardio-metabolic disease. Rare variant associations facilitate fine-mapping of causal alleles, but their contribution to fat distribution is understudied. We performed a genome-wide scan of rare nonsynonymous variants for body mass index-adjusted waist-to-hip-ratio (BMI-adjusted WHR; a widely-used measure of fat distribution) in 450,562 European ancestry individuals, followed by systematic Bayesian fine-mapping at six genome-wide (p<5x10-08; main-analysis) and two subthreshold signals (significant at a Bonferroni-corrected p<1.3x10-06). We found strong statistical evidence of causal association for nonsynonymous alleles in CALCRL (p.L87P, pconditional=5.9x10-12; posterior-probability of association [PPA]=52%), PLIN1 (p.L90P, pconditional=5.5x10-13; PPA>99%), PDE3B (p.R783X, pconditional=6.2x10-15; PPA>99%), ACVR1C (p.I195T; pconditional=5.4x10-12; PPA>99%), and FGF1 (p.G21E, pconditional=1.6x10-07; PPA=98%). Alleles at the four likely-causal main-analysis genes affected fat distribution primarily via larger hip-rather than smaller waist-circumference and six of nine conditionally-independent WHR-lowering index-variants were associated with protection from cardiovascular or metabolic disease. All four genes are expressed in adipose tissue and have been linked with the regulation of intracellular lipolysis, which controls fat retention in mature cells. Targeted follow-up analyses of key intracellular-lipolysis genes revealed associations for a variant in the initiator of intracellular lipolysis PNPLA2 (p.N252K) with higher BMI-adjusted-WHR and higher cardio-metabolic risk. This study provides human genetic evidence of a link between intracellular lipolysis, fat-distribution and its cardio-metabolic complications in the general population.

genetics↗