Fatty Acid Metabolism and Derived-Mediators Distinctive of PPAR-α Activation in Obese Subjects Post Bariatric Surgery

Abstract

Bariatric surger (BS) is characterized by lipid metabolic changes as a response to the massive release of non-esterified fatty acids (NEFA) from adipose depots. The study aimed at evaluating changes in polyunsaturated fatty acids (PUFA) metabolism and biosynthesis of the lipid mediators N-acylethanolamines (NAE), as indices of nuclear peroxisome proliferator-activated receptor (PPAR)-α activation. The observational study was performed on 35 subjects (27 female, 8 male) with obesity, undergoing bariatric surgery. We assessed plasma FA and NAE profiles by LC-MS/MS, clinical parameters and anthropometric measures before and 1 and 6 months after bariatric surgery. One month after bariatric surgery, as body weight and clinical parameters improved significantly, we found higher plasma levels of N-oleoylethanolamine, arachidonic and a 22:6-n3/20:5-n3 ratio as evidence of PPAR-α activation. These changes corresponded to higher circulating levels of NEFA and a steep reduction of the fat mass. After 6 months 22:6-n3/20:5-n3 remained elevated and fat mass was further reduced. Our data suggest that the massive release of NEFA from adipose tissue at 1-Post, possibly by inducing PPAR-α, may enhance FA metabolism contributing to fat depot reduction and improved metabolic parameters in the early stage. However, PUFA metabolic changes favor n6 PUFA biosynthesis, requiring a nutritional strategy aimed at reducing the n6/n3 PUFA ratio.

Keywords: N-oleoylethanolamine (OEA); bariatric surgery; non-esterified fatty acid (NEFA); obesity; peroxisome proliferator-activated receptor (PPAR)-α.

Scheme 1

Study design and experimental procedure. Discrepancy in number of subjects, n, in data analysis are due to the limited sample amount available and/or their loss during the analysis procedure. Body mass index (BMI), free fat mass (FFM), fat mass (FM), neck (NC), waist (WC), hip (HC) circumferences, triglycerides (TG), LDL-cholesterol (LDL-Chol), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), endocannabinoids (EC), N-acylethanolamine (NAE) non-esterified fatty acids (NEFA), fatty acids (FA).

Figure 1

Values of body weight (A), body mass index (BMI, (B)), free fat mass (FFM, (C)), fat mass (FM, (D)), neck (E), waist (F), and hip (G) circumferences and waist-to-hip ratio (H) in subjects at baseline (Pre), one month (1 Post) and six months (6 Post) after bariatric surgery. Values are presented as boxes (mean value) and whiskers (higher and lower values) (Body weight n = 35; BMI n = 35; FFM kg n = 33; FM kg n = 33; NC n = 33; WC n = 33; HC n = 33). ** p < 0.01; *** p < 0.001; **** p < 0.0001.

Figure 2

Values of N-arachidonoylethanolamine (AEA, (A)), 2-arachidonoylglycerol (2-AG, (B)), N-oleoylethanolamine (OEA, (C)), N-acylethanolamine (NAE, (D)), expressed as mol % of total fatty acid (FA), in subjects at baseline (Pre), one month (1 Post) and six months (6 Post) after bariatric surgery. Values are presented as boxes (mean value) and whiskers (higher and lower values) (AEA n = 28; 2AG n = 27; OEA n = 27; NAE n = 27). * p < 0.05; ** p < 0.01; *** p < 0.001.

Figure 3

Plasma FA and *n3 HUFA scores in subjects at baseline (Pre), one month (1 Post) and six months (6 Post) after bariatric surgery. Values, expressed as mol % of total fatty acid (FA), are presented as boxes (mean value) and whiskers (higher and lower values) (n = 33). ** p < 0.01; *** p < 0.001; **** p < 0.0001.

Figure 4

Ratios of 22:6-n3/20:5-n3 (A) [31,33], and 20:4-n6/18:2-n6 (B) [36] in subjects at baseline (Pre), one month (1 Post) and six months (6 Post) after bariatric surgery. Values, expressed as mol % of total fatty acid (FA), are presented as boxes (mean value) and whiskers (higher and lower values) (n = 33). *** p < 0.001; **** p < 0.0001.

Figure 5

Values of non-esterified fatty acid (NEFA) (A) and 16:1/18:2 (B) [30] expressed as nmol/mL of plasma in participants at baseline (Pre), one month (1 Post) and six months (6 Post) after bariatric surgery. Values are presented as boxes (mean value) and whiskers (higher and lower values) (n = 30). * p < 0.05; **** p < 0.0001.

Figure 6

The increased NEFA released from adipose tissue may activate PPAR-α which induces PUFA metabolism, FA β-oxidation and increased circulating OEA levels further enhance PPAR-α activation and hence induce body weight loss and improved glucose and lipid metabolism. In red the putative mechanism which may explain why four subjects (12%) did not respond in the same way to circulating NEFA, leading us to hypothesize a ’’resistance’’ to PPAR-α activation. Red, PPAR-α non responder subjects; Blue, PPAR-α responder subjects; ↑, increase; ↓, decrease; +, positive regulation; -, negative regulation; ≈, unchanged.