Endoplasmic reticulum stress activation in adipose tissue induces metabolic syndrome in individuals with familial partial lipodystrophy of the Dunnigan type

Abstract

Background: Familial partial lipodystrophy of the Dunnigan type is one of the most common inherited lipodystrophies variables. These individuals have important metabolic disorders that cause predisposition to various diseases. In this study we aimed to demonstrate the relation between the metabolic abnormalities, inflammatory profile and the expression of genes involved in the activation of the endoplasmic reticulum stress (ERS) in subjects with FPLD.

Methods: We evaluated 14 female FPLD patients and compared with 13 female healthy individuals. The subjects were paired with their respective BMI and age and categorized into two groups: Familial partial lipodystrophy of the Dunnigan type (FPLD) and control. Patients were fasted for 12 h before blood collection for measurement of HbA1c, glucose, insulin, lipids and inflammatory markers. Subcutâneous adipose tissue was collected by puncture aspiration of submental region during ambulatorial surgical aesthetic procedure.

Results: We demonstrate that patients with FPLD show increased HbA1c (p < 0.01), fasting glucose (p < 0.002) and triglycerides (p < 0.005) while HDL/cholesterol (p < 0.001) was lower when compared to healthy individuals. We found that 64.2% FPLD patients had metabolic syndrome according to International Diabetes Federation definition. We also observe increased AUC of glucose (p < 0.001) and insulin during oGTT, featuring a frame of hyperglycemia and hyperinsulinemia, suggesting insulin resistance. Also we found hyperactivation of several genes responsible for ERS such as ATF-4 (p < 0.01), ATF-6 (p < 0.01), EIF2α3K (p < 0.005), CCT4 (p < 0.001), CHOP (p < 0.01), CALR (p < 0.001) and CANX (p < 0.005), that corroborate the idea that diabetes mellitus and metabolic syndrome are associated with direct damage to the endoplasmic reticulum homeostasis. Ultimately, we note that individuals with lipodystrophy have an increase in serum interleukins, keys of the inflammatory process, as IL-1β, TNF-α and IL-6 (p < 0.05 all), compared with healthy individuals, which can be the trigger to insulin resistance in this population.

Conclusion: Individuals with FPLD besides having typical dysfunctions of metabolic syndrome, show a hyperactivation of ERS associated with increased systemic inflammatory profile, which together may explain the complex clinical aspect of this diseases.Trial registration HCRP no 6711/2012.

Keywords: Dunnigan type; Endoplasmic reticulum stress; Familial partial lipodystrophy; Insulin resistance.

Fig. 1

Lipodystrophy induces changes in serum levels of various blood metabolites. Individuals with FPLD have high blood metabolic parameters in comparison with control subjects. a Quantification of glycated hemoglobin levels. Student’s t test **p < 0.01. b Quantification of serum triglyceride levels. Student’s t test ***p < 0.005. c Evaluation of the amount of blood cholesterol. Student’s t test (ns). d Quantification of serum LDL levels. Student’s t test (ns). e Quantification of HDL levels. Student’s t test ****p < 0.001. Control group (n = 13), FPLD group (n = 14)

Fig. 2

Oral Glucose Tolerance Test demonstrates the uncontrolled glycemic regulation and reduced insulin secretion. a Graph showing glucose levels during oGTT. The individuals in the FPLD group presented increased glucose levels in compared to control group. ***p < 0.005, ****p < 0.001. b Quantification of the insulin secretion during OTG. The FPLD group presented delayed insulin secretion compared to the control group *p < 0.05. c Area under the curve of oGTT graphs (plasma glucose and insulin). The AUC of glucose graph showed that individuals of FPLD group have higher AUC in compared to control group, demonstrating the uncontrolled glycemic; however no observed differences in insulin AUC. Student’s t test ****p < 0.001. d Evaluation of serum C-Reactive Protein levels. Student’s t test *p < 0.05. Control group (n = 13) and FPLD group (n = 14)

Fig. 3

Interleukins responsible for the inflammatory profile are increased in the serum of individuals with FPLD. The levels of the main interleukins inflammatory process are altered in the serum of patients with FPLD. a IL-1β quantification in the serum of individuals with FPLD and control subjects. Student’s t test *p < 0.05. b Serum TNF-α quantification of FPLD individuals and control. Student’s t test *p < 0.05. c Measurement of IL-6 concentration in the serum of FPLD individuals and control. Student’s t test *p < 0.05. Control group (n = 13) and FPLD group (n = 14)

Fig. 4

Metabolic changes in adipose tissue in FPLD subjects. Gene expression in adipose tissue in response FPLD. Control group (n = 4) and FPLD group (n = 5), paired with the same age and BMI. Total RNA was analyzed by real-time qPCR; data represented mean ± SEM. Student’s t test ****p < 0.001 versus control, **p < 0.01, ***p < 0.005