Resting Energy Expenditure, Insulin Resistance and UCP1 Expression in Human Subcutaneous and Visceral Adipose Tissue of Patients With Obesity

Abstract

Determinants of resting energy expenditure (REE) in humans are still under investigation, especially the association with insulin resistance. Brown adipose tissue (AT) regulates energy expenditure through the activity of the uncoupling protein 1 (UCP1). White AT browning is the process by which some adipocytes within AT depots acquire properties of brown adipocytes ("brite" adipocytes) and it correlates with metabolic improvement. We analyzed determinants of REE in patients with obesity and assessed UCP1 expression as a "brite" marker in abdominal subcutaneous AT (SAT) and visceral omental AT (VAT). Clinical data, REE, free fat mass (FFM), and fat mass (FM) were determined in 209 patients with obesity. UCP1, PPARG coactivator 1 alpha (PPARGC1A), transcription factor A, mitochondrial (TFAM), T-box transcription factor 1 (TBX1), and solute carrier family 27 member 1 (SLC27A1) expression was assayed in SAT and VAT samples, obtained during sleeve gastrectomy from 62 patients with obesity. REE and body composition data were also available for a subgroup of 35 of whom. In 209 patients with obesity a multiple regression model was computed with REE as the dependent variable and sex, waist, FFM, FM, homeostasis model assessment-insulin resistance (HOMA), interleukin-6 and High Density Lipoprotein-cholesterol as the independent variables. Only FFM, FM and HOMA were independently correlated with REE (r = 0.787, AdjRsqr = 0.602). In each patient VAT displayed a higher UCP1, PPARGC1A, TFAM, TBX1, and SLC27A1 expression than SAT and UCP1 expression in VAT (UCP1-VAT) correlated with Body Mass Index (BMI) (r = 0.287, p < 0.05). Introducing UCP1-VAT in the multivariate model, we showed that FFM, HOMA, interleukin-6, High Density Lipoprotein-cholesterol, and UCP1-VAT were independent factors correlated with REE (r = 0.736, AdjRsqr = 0.612). We confirmed that REE correlates with FFM, FM and HOMA in a large cohort of patients. Our results clearly showed that UCP1-VAT expression was significantly increased in severe human obesity (BMI > 50 kg/m²) and that it behaved as an independent predictor of REE. Lastly, we suggest that an increased REE and browning in metabolically complicated severe obesity could represent an effort to counteract further weight gain.

Keywords: UCP1; adipose tissue; browning; insulin resistance; obesity; resting energy expenditure.

Figure 1

Study design. PWO, Patients with Obesity; REE, resting energy expenditure; SAT, subcutaneous Adipose Tissue; VAT, visceral omental Adipose Tissue; UCP1, uncoupling protein 1.

Figure 2

Gene expression in paired subcutaneous and visceral adipose tissue of patients with severe obesity. UCP1 (A), PPARGC1A (B), TFAM (C), TBX1 (D), SLC27A1 (E) mRNA were quantified by qPCR and normalized for HMBS mRNA in SAT and VAT depots for each of 62 patients with severe obesity described in Table 1. For UCP1 expression, the positive samples were 23/62 for SAT and 61/62 for VAT. Results were presented as a box plot, with 25th, 75th percentile and median values. Statistical analysis was performed by the Mann-Whitney U-test (***p < 0.0001).

Figure 3

Correlation between UCP1 expression in visceral omental adipose tissue and BMI. UCP1 mRNA expression quantified by qPCR and normalized to HMBS mRNA was correlated with BMI in 61 patients with severe obesity. Statistical analysis was performed by Pearson correlation. The dotted line represents the BMI cut-off of 50 kg/m² used to divide patients in Figure 4.

Figure 4

Increased UCP1 expression in visceral omental adipose tissue of patients with BMI higher than 50 kg/m². UCP1 mRNA was quantified in VAT by qPCR, normalized for HMBS and compared in PWO with BMI lower than 50 (n = 43) and with BMI higher that 50 (n = 18). Data were reported as a box plot, with 25th, 75th percentile and median values. Statistical analysis was performed by the Mann-Whitney U-test (**p < 0.01).