Abstract
Objective. Similar to obesity, lipodystrophy (LD) causes adipose tissue dysfunction and severe metabolic complications. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor β superfamily and is dysregulated in metabolic disease including obesity and diabetes mellitus. Circulating levels in LD and the impact of leptin treatment have not been investigated so far. Material and Methods. GDF15 serum levels were quantified in 60 LD patients without human immunodeficiency virus infection and 60 controls matched for age, gender, and body mass index. The impact of metreleptin treatment on circulating GDF15 was assessed in a subgroup of patients. GDF15 mRNA expression was determined in metabolic tissues of leptin-deficient lipodystrophic aP2-nSREBP1c-Tg mice, obese ob/ob mice, and control C57Bl6 mice. Results. Median GDF15 serum concentrations were significantly higher in LD patients (819 ng/L) as compared to the control group (415 ng/L) (p < 0.001). In multiple linear regression analysis, an independent and positive association remained between GDF15 on one hand and age, patient group, hemoglobin A1c, triglycerides, and C-reactive protein on the other hand. Moreover, there was an independent negative association between GFD15 and estimated glomerular filtration rate. Circulating GDF15 was not significantly affected by metreleptin treatment in LD patients. Gdf15 was upregulated in leptin-deficient lipodystrophic mice as compared to controls. Moreover, Gdf15 mRNA expression was downregulated by leptin treatment in lipodystrophic and obese animals. Conclusions. Serum concentrations of GDF15 are elevated in LD patients and independently associated with markers of metabolic dysfunction. Gdf15 expression is higher in lipodystrophic mice and downregulated by leptin treatment.
Highlights
Adipocyte hypertrophy and hyperplasia in obesity causes adipose tissue (AT) dysfunction and severe metabolic complications including dyslipidemia, nonalcoholic fatty liver disease, insulin resistance, diabetes mellitus, and coronary heart disease [1]
Adiponectin and leptin serum levels are significantly lower in LD patients than in controls (p < 0.001; Table 1), while serum concentrations of fibroblast growth factor (FGF) 21 are significantly elevated in the LD group compared to controls (p = 0.002; Table 1)
We demonstrate for the first time that circulating Growth differentiation factor 15 (GDF15) concentrations are significantly higher in LD patients as compared to age, gender, and body mass index (BMI)-matched controls
Summary
Adipocyte hypertrophy and hyperplasia in obesity causes adipose tissue (AT) dysfunction and severe metabolic complications including dyslipidemia, nonalcoholic fatty liver disease, insulin resistance, diabetes mellitus, and coronary heart disease [1]. Thereby, AT in LD has limited storage capacity for energy in terms of triacylglycerols. This leads to ectopic fat deposition predominantly in liver, pancreas and muscle [3]. In addition—and similar to obesity—AT paucity causes dysregulation of several endocrine adipocyte-derived factors, e.g., leptin and adiponectin, which are critical for the adequate regulation of glucose metabolism and energy homeostasis [4,5]. Supplementation of leptin resulted in significant improvements of glucose and lipid metabolism in LD animal models and in LD affected humans [6,7].
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