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Extracellular fatty acid synthase: a possible surrogate biomarker of insulin resistance.

Fernandez-Real JM, Menendez JA, Moreno-Navarrete JM, Blüher M, Vazquez-Martin A, Vázquez MJ, Ortega F, Diéguez C, Frühbeck G, Ricart W, Vidal-Puig A - Diabetes (2010)

Bottom Line: Circulating fatty acid synthase (FASN) is a biomarker of metabolically demanding human diseases.Both visceral and subcutaneous FASN expression and protein levels correlated inversely with extracellular circulating FASN (P = -0.63; P < 0.0001), suggesting that circulating FASN is linked to depletion of intracellular FASN.Rosiglitazone did not lead to significant changes in circulating FASN concentration.

View Article: PubMed Central - PubMed

Affiliation: Department of Diabetes, Endocrinology and Nutrition, Institutd' Investigació Biomédica de Girona, CIBEROBN Fisiopatología de la Obesidad y Nutrición CB06/03/010, Girona, Catalonia, Spain. jmfernandezreal.girona.ics@gencat.cat

ABSTRACT

Context: Circulating fatty acid synthase (FASN) is a biomarker of metabolically demanding human diseases. The aim of this study was to determine whether circulating FASN could be a biomarker of overnutrition-induced metabolic stress and insulin resistance in common metabolic disorders.

Research design and methods: Circulating FASN was evaluated in two cross-sectional studies in association with insulin sensitivity and in four longitudinal studies investigating the effect of diet- and surgery-induced weight loss, physical training, and adipose tissue expansion using peroxisome proliferator-activated receptor agonist rosiglitazone on circulating FASN.

Results: Age- and BMI-adjusted FASN concentrations were significantly increased in association with obesity-induced insulin resistance in two independent cohorts. Both visceral and subcutaneous FASN expression and protein levels correlated inversely with extracellular circulating FASN (P = -0.63; P < 0.0001), suggesting that circulating FASN is linked to depletion of intracellular FASN. Improved insulin sensitivity induced by therapeutic strategies that decreased fat mass (diet induced, surgery induced, or physical training) all led to decreased FASN levels in blood (P values between 0.02 and 0.04). To discriminate whether this was an effect related to insulin sensitization, we also investigated the effects of rosiglitazone. Rosiglitazone did not lead to significant changes in circulating FASN concentration.

Conclusions: Our results suggest that circulating FASN is a biomarker of overnutrition-induced insulin resistance that could provide diagnostic and prognostic advantages by providing insights on the individualized metabolic stress.

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Related in: MedlinePlus

A: Linear association between circulating FASN concentration and insulin sensitivity according to glucose tolerance status (upper panel: normal glucose tolerance; lower panel: altered glucose tolerance). Although the absolute value of circulating FASN is reported, the statistical analysis was performed using its log-transformed value. B: Linear association between log circulating FASN concentration and insulin sensitivity in all subjects (solid line with 95% CI) and according to glucose tolerance status (dotted lines). The association was also significant in each subgroup separately (r = −0.43, P = 0.01, in subjects with normal glucose tolerance [NGT] and r = −0.39, P = 0.02, in subjects with type 2 diabetes).
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Figure 2: A: Linear association between circulating FASN concentration and insulin sensitivity according to glucose tolerance status (upper panel: normal glucose tolerance; lower panel: altered glucose tolerance). Although the absolute value of circulating FASN is reported, the statistical analysis was performed using its log-transformed value. B: Linear association between log circulating FASN concentration and insulin sensitivity in all subjects (solid line with 95% CI) and according to glucose tolerance status (dotted lines). The association was also significant in each subgroup separately (r = −0.43, P = 0.01, in subjects with normal glucose tolerance [NGT] and r = −0.39, P = 0.02, in subjects with type 2 diabetes).

Mentions: Cross-sectional studies revealed that age- and BMI-adjusted serum FASN concentrations were inversely associated with insulin sensitivity in two independent cohorts of subjects. In the first cohort, the association was significant in all subjects as a whole (r = −0.20; P = 0.02), especially in subjects with altered glucose tolerance (r = −0.44; P = 0.004) (Fig. 2A). In the second cohort, the association was highly significant (r = −0.60; P < 0.0001) (Fig. 2B). As hypothesized, the highest levels of FASN concentrations in serum were observed in obese subjects with altered glucose tolerance (online appendix Table 1). Also in support of our hypothesis, FASN gene expression in visceral and subcutaneous adipose tissue correlated negatively with extracellular FASN in the obese glucose-intolerant group of subjects (r = −0.44, P < 0.01, and r = −0.31, P < 0.05, respectively). As expected, these results were especially robust in the extreme of the spectrum corresponding with obese subjects who had developed type 2 diabetes (r = −0.63; P < 0.0001) (Fig. 3A). The relevance of these findings was confirmed with the protein levels in serum (Fig. 3B) and adipose tissue (not shown). This indicates that under metabolic stress and in association with insulin resistance, intracellular levels of FASN may decrease by the combined effects of decreased biosynthesis coupled with increased secretion of FASN protein, leading to increased plasma levels.


Extracellular fatty acid synthase: a possible surrogate biomarker of insulin resistance.

Fernandez-Real JM, Menendez JA, Moreno-Navarrete JM, Blüher M, Vazquez-Martin A, Vázquez MJ, Ortega F, Diéguez C, Frühbeck G, Ricart W, Vidal-Puig A - Diabetes (2010)

A: Linear association between circulating FASN concentration and insulin sensitivity according to glucose tolerance status (upper panel: normal glucose tolerance; lower panel: altered glucose tolerance). Although the absolute value of circulating FASN is reported, the statistical analysis was performed using its log-transformed value. B: Linear association between log circulating FASN concentration and insulin sensitivity in all subjects (solid line with 95% CI) and according to glucose tolerance status (dotted lines). The association was also significant in each subgroup separately (r = −0.43, P = 0.01, in subjects with normal glucose tolerance [NGT] and r = −0.39, P = 0.02, in subjects with type 2 diabetes).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874712&req=5

Figure 2: A: Linear association between circulating FASN concentration and insulin sensitivity according to glucose tolerance status (upper panel: normal glucose tolerance; lower panel: altered glucose tolerance). Although the absolute value of circulating FASN is reported, the statistical analysis was performed using its log-transformed value. B: Linear association between log circulating FASN concentration and insulin sensitivity in all subjects (solid line with 95% CI) and according to glucose tolerance status (dotted lines). The association was also significant in each subgroup separately (r = −0.43, P = 0.01, in subjects with normal glucose tolerance [NGT] and r = −0.39, P = 0.02, in subjects with type 2 diabetes).
Mentions: Cross-sectional studies revealed that age- and BMI-adjusted serum FASN concentrations were inversely associated with insulin sensitivity in two independent cohorts of subjects. In the first cohort, the association was significant in all subjects as a whole (r = −0.20; P = 0.02), especially in subjects with altered glucose tolerance (r = −0.44; P = 0.004) (Fig. 2A). In the second cohort, the association was highly significant (r = −0.60; P < 0.0001) (Fig. 2B). As hypothesized, the highest levels of FASN concentrations in serum were observed in obese subjects with altered glucose tolerance (online appendix Table 1). Also in support of our hypothesis, FASN gene expression in visceral and subcutaneous adipose tissue correlated negatively with extracellular FASN in the obese glucose-intolerant group of subjects (r = −0.44, P < 0.01, and r = −0.31, P < 0.05, respectively). As expected, these results were especially robust in the extreme of the spectrum corresponding with obese subjects who had developed type 2 diabetes (r = −0.63; P < 0.0001) (Fig. 3A). The relevance of these findings was confirmed with the protein levels in serum (Fig. 3B) and adipose tissue (not shown). This indicates that under metabolic stress and in association with insulin resistance, intracellular levels of FASN may decrease by the combined effects of decreased biosynthesis coupled with increased secretion of FASN protein, leading to increased plasma levels.

Bottom Line: Circulating fatty acid synthase (FASN) is a biomarker of metabolically demanding human diseases.Both visceral and subcutaneous FASN expression and protein levels correlated inversely with extracellular circulating FASN (P = -0.63; P < 0.0001), suggesting that circulating FASN is linked to depletion of intracellular FASN.Rosiglitazone did not lead to significant changes in circulating FASN concentration.

View Article: PubMed Central - PubMed

Affiliation: Department of Diabetes, Endocrinology and Nutrition, Institutd' Investigació Biomédica de Girona, CIBEROBN Fisiopatología de la Obesidad y Nutrición CB06/03/010, Girona, Catalonia, Spain. jmfernandezreal.girona.ics@gencat.cat

ABSTRACT

Context: Circulating fatty acid synthase (FASN) is a biomarker of metabolically demanding human diseases. The aim of this study was to determine whether circulating FASN could be a biomarker of overnutrition-induced metabolic stress and insulin resistance in common metabolic disorders.

Research design and methods: Circulating FASN was evaluated in two cross-sectional studies in association with insulin sensitivity and in four longitudinal studies investigating the effect of diet- and surgery-induced weight loss, physical training, and adipose tissue expansion using peroxisome proliferator-activated receptor agonist rosiglitazone on circulating FASN.

Results: Age- and BMI-adjusted FASN concentrations were significantly increased in association with obesity-induced insulin resistance in two independent cohorts. Both visceral and subcutaneous FASN expression and protein levels correlated inversely with extracellular circulating FASN (P = -0.63; P < 0.0001), suggesting that circulating FASN is linked to depletion of intracellular FASN. Improved insulin sensitivity induced by therapeutic strategies that decreased fat mass (diet induced, surgery induced, or physical training) all led to decreased FASN levels in blood (P values between 0.02 and 0.04). To discriminate whether this was an effect related to insulin sensitization, we also investigated the effects of rosiglitazone. Rosiglitazone did not lead to significant changes in circulating FASN concentration.

Conclusions: Our results suggest that circulating FASN is a biomarker of overnutrition-induced insulin resistance that could provide diagnostic and prognostic advantages by providing insights on the individualized metabolic stress.

Show MeSH
Related in: MedlinePlus