西亚试剂：HBM-Causing LRP5 Mutations Are Associated with Lower-Body F

HBM-Causing LRP5 Mutations Are Associated with Lower-Body Fat Accumulation
We examined the adipose and metabolic phenotype of three pedigrees with extreme HBM secondary to rare heterozygous GoF LRP5 mutations. Compared to age-, gender-, and BMI-matched Oxford Biobank (OBB) controls, HBM LRP5 mutation carriers had an increased amount of lower-body fat as determined by whole-body dual energy X-ray absorptiometry (DXA). In particular, all overweight/obese (BMI ≥ 25) HBM subjects with LRP5 mutations (n = 5 of 6 individuals in total; S1–S3, S5, S6) had a higher tissue percent fat specifically in their legs ( Table 1). Furthermore, all affected individuals displayed lower android/leg, android/total, and central/peripheral fat mass ratios (Table 1). This adipose phenotype was not driven by the HBM, as HBM LRP5 mutation carriers had a decreased upper-to-lower-body fat ratio even when compared with matched non-LRP5 HBM cases (n = 18) ( Table 2). Similar results were obtained when comparing age-, gender-, and BMI-adjusted DXA data from LRP5 HBM cases versus the rest of the (non-LRP5) HBM cohort (n = 134) ( Table S1). LRP5 HBM individuals also exhibited enhanced insulin sensitivity as determined by lower HOMA-IR and fasting insulin levels relative to OBB controls ( Tables 1 and S2). One exception was subject S2 (68 years old), whom we were able to compare only with 49–50 year old gender- and BMI-matched controls. Finally, ex vivo gene expression analyses of fractionated SC adipose cells revealed lower inflammatory gene transcript levels in LRP5 HBM individuals (n = 4; subjects S1, S4–S6) versus OBB controls (n = 24–25) ( Figure S1A). We conclude that rare, GoF LRP5 mutations are associated with enhanced lower-body fat accumulation, a favorable metabolic profile, and reduced WAT inflammation.

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