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Downregulation of adipose tissue fatty acid trafficking in obesity: a driver for ectopic fat deposition?

McQuaid SE, Hodson L, Neville MJ, Dennis AL, Cheeseman J, Humphreys SM, Ruge T, Gilbert M, Fielding BA, Frayn KN, Karpe F - Diabetes (2010)

Bottom Line: Lipotoxicity and ectopic fat deposition reduce insulin signaling.Abdominally obese men had substantially (2.5-fold) greater adipose tissue mass than lean control subjects, but the rates of delivery of nonesterified fatty acids (NEFA) were downregulated, resulting in normal systemic NEFA concentrations over a 24-h period.However the implicit reduction in adipose tissue fatty acid uptake goes beyond this and shows a maladaptive response with a severely impaired pathway for direct dietary fat storage.

View Article: PubMed Central - PubMed

Affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford, UK.

ABSTRACT

Objective: Lipotoxicity and ectopic fat deposition reduce insulin signaling. It is not clear whether excess fat deposition in nonadipose tissue arises from excessive fatty acid delivery from adipose tissue or from impaired adipose tissue storage of ingested fat.

Research design and methods: To investigate this we used a whole-body integrative physiological approach with multiple and simultaneous stable-isotope fatty acid tracers to assess delivery and transport of endogenous and exogenous fatty acid in adipose tissue over a diurnal cycle in lean (n = 9) and abdominally obese men (n = 10).

Results: Abdominally obese men had substantially (2.5-fold) greater adipose tissue mass than lean control subjects, but the rates of delivery of nonesterified fatty acids (NEFA) were downregulated, resulting in normal systemic NEFA concentrations over a 24-h period. However, adipose tissue fat storage after meals was substantially depressed in the obese men. This was especially so for chylomicron-derived fatty acids, representing the direct storage pathway for dietary fat. Adipose tissue from the obese men showed a transcriptional signature consistent with this impaired fat storage function.

Conclusions: Enlargement of adipose tissue mass leads to an appropriate downregulation of systemic NEFA delivery with maintained plasma NEFA concentrations. However the implicit reduction in adipose tissue fatty acid uptake goes beyond this and shows a maladaptive response with a severely impaired pathway for direct dietary fat storage. This adipose tissue response to obesity may provide the pathophysiological basis for ectopic fat deposition and lipotoxicity.

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The rate of appearance (Ra) of NEFA in lean and abdominally obese men shown as total body Ra and adjusted for lean and fat mass, respectively. The Ra of NEFA: whole-body (A), expressed per lean mass (B), and per total fat mass (C) in lean (●) and abdominally obese men (○). Three meals were given as indicated by the dotted vertical lines. The Ra of NEFA (μmol/min) was significantly higher in the abdominally obese group compared with the lean group (A) (time × group, P = 0.009). When the data were calculated and expressed as rate of disappearance (Rd) of NEFA, i.e., normalized per lean body mass (μmol · min−1 [lean mass (kg)]−1), this difference disappeared (P = 0.14). The abdominally obese men had significantly lower Ra of NEFA when expressed per total fat mass (μmol · min−1 [fat mass (kg)]−1, P = 0.029).
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Figure 2: The rate of appearance (Ra) of NEFA in lean and abdominally obese men shown as total body Ra and adjusted for lean and fat mass, respectively. The Ra of NEFA: whole-body (A), expressed per lean mass (B), and per total fat mass (C) in lean (●) and abdominally obese men (○). Three meals were given as indicated by the dotted vertical lines. The Ra of NEFA (μmol/min) was significantly higher in the abdominally obese group compared with the lean group (A) (time × group, P = 0.009). When the data were calculated and expressed as rate of disappearance (Rd) of NEFA, i.e., normalized per lean body mass (μmol · min−1 [lean mass (kg)]−1), this difference disappeared (P = 0.14). The abdominally obese men had significantly lower Ra of NEFA when expressed per total fat mass (μmol · min−1 [fat mass (kg)]−1, P = 0.029).

Mentions: The diurnal NEFA delivery curves were essentially parallel between the groups. Although the fasting rate (790 ± 100 [lean] vs. 970 ± 130 μmol/min [abdominally obese]) was not statistically different between the groups, the time-averaged diurnal effect was very clear (450 ± 35 vs. 650 ± 50 μmol/min, P = 0.009) (Fig. 2A). Both groups showed an immediate reduction in NEFA delivery in response to the breakfast: the NEFA delivery was reduced by 38 ± 6% (P = 0.002) in the lean group with a less distinct response in the abdominally obese group (−19 ± 10%, P = 0.046). Expressed as NEFA disappearance per unit of lean body mass, the difference between the groups disappeared (Fig. 2B). The rationale behind this is based on the assumption that NEFA delivery equals NEFA catabolism and that lean body mass is proportional to the skeletal muscle and the liver. However, normalizing the NEFA delivery to fat mass, the abdominally obese group showed markedly lower fasting as well as time-averaged diurnal NEFA delivery compared with the lean group (Fig. 2C). This highlights the downregulation of NEFA delivery from the expanded adipose tissue in the abdominally obese state.


Downregulation of adipose tissue fatty acid trafficking in obesity: a driver for ectopic fat deposition?

McQuaid SE, Hodson L, Neville MJ, Dennis AL, Cheeseman J, Humphreys SM, Ruge T, Gilbert M, Fielding BA, Frayn KN, Karpe F - Diabetes (2010)

The rate of appearance (Ra) of NEFA in lean and abdominally obese men shown as total body Ra and adjusted for lean and fat mass, respectively. The Ra of NEFA: whole-body (A), expressed per lean mass (B), and per total fat mass (C) in lean (●) and abdominally obese men (○). Three meals were given as indicated by the dotted vertical lines. The Ra of NEFA (μmol/min) was significantly higher in the abdominally obese group compared with the lean group (A) (time × group, P = 0.009). When the data were calculated and expressed as rate of disappearance (Rd) of NEFA, i.e., normalized per lean body mass (μmol · min−1 [lean mass (kg)]−1), this difference disappeared (P = 0.14). The abdominally obese men had significantly lower Ra of NEFA when expressed per total fat mass (μmol · min−1 [fat mass (kg)]−1, P = 0.029).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3012196&req=5

Figure 2: The rate of appearance (Ra) of NEFA in lean and abdominally obese men shown as total body Ra and adjusted for lean and fat mass, respectively. The Ra of NEFA: whole-body (A), expressed per lean mass (B), and per total fat mass (C) in lean (●) and abdominally obese men (○). Three meals were given as indicated by the dotted vertical lines. The Ra of NEFA (μmol/min) was significantly higher in the abdominally obese group compared with the lean group (A) (time × group, P = 0.009). When the data were calculated and expressed as rate of disappearance (Rd) of NEFA, i.e., normalized per lean body mass (μmol · min−1 [lean mass (kg)]−1), this difference disappeared (P = 0.14). The abdominally obese men had significantly lower Ra of NEFA when expressed per total fat mass (μmol · min−1 [fat mass (kg)]−1, P = 0.029).
Mentions: The diurnal NEFA delivery curves were essentially parallel between the groups. Although the fasting rate (790 ± 100 [lean] vs. 970 ± 130 μmol/min [abdominally obese]) was not statistically different between the groups, the time-averaged diurnal effect was very clear (450 ± 35 vs. 650 ± 50 μmol/min, P = 0.009) (Fig. 2A). Both groups showed an immediate reduction in NEFA delivery in response to the breakfast: the NEFA delivery was reduced by 38 ± 6% (P = 0.002) in the lean group with a less distinct response in the abdominally obese group (−19 ± 10%, P = 0.046). Expressed as NEFA disappearance per unit of lean body mass, the difference between the groups disappeared (Fig. 2B). The rationale behind this is based on the assumption that NEFA delivery equals NEFA catabolism and that lean body mass is proportional to the skeletal muscle and the liver. However, normalizing the NEFA delivery to fat mass, the abdominally obese group showed markedly lower fasting as well as time-averaged diurnal NEFA delivery compared with the lean group (Fig. 2C). This highlights the downregulation of NEFA delivery from the expanded adipose tissue in the abdominally obese state.

Bottom Line: Lipotoxicity and ectopic fat deposition reduce insulin signaling.Abdominally obese men had substantially (2.5-fold) greater adipose tissue mass than lean control subjects, but the rates of delivery of nonesterified fatty acids (NEFA) were downregulated, resulting in normal systemic NEFA concentrations over a 24-h period.However the implicit reduction in adipose tissue fatty acid uptake goes beyond this and shows a maladaptive response with a severely impaired pathway for direct dietary fat storage.

View Article: PubMed Central - PubMed

Affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford, UK.

ABSTRACT

Objective: Lipotoxicity and ectopic fat deposition reduce insulin signaling. It is not clear whether excess fat deposition in nonadipose tissue arises from excessive fatty acid delivery from adipose tissue or from impaired adipose tissue storage of ingested fat.

Research design and methods: To investigate this we used a whole-body integrative physiological approach with multiple and simultaneous stable-isotope fatty acid tracers to assess delivery and transport of endogenous and exogenous fatty acid in adipose tissue over a diurnal cycle in lean (n = 9) and abdominally obese men (n = 10).

Results: Abdominally obese men had substantially (2.5-fold) greater adipose tissue mass than lean control subjects, but the rates of delivery of nonesterified fatty acids (NEFA) were downregulated, resulting in normal systemic NEFA concentrations over a 24-h period. However, adipose tissue fat storage after meals was substantially depressed in the obese men. This was especially so for chylomicron-derived fatty acids, representing the direct storage pathway for dietary fat. Adipose tissue from the obese men showed a transcriptional signature consistent with this impaired fat storage function.

Conclusions: Enlargement of adipose tissue mass leads to an appropriate downregulation of systemic NEFA delivery with maintained plasma NEFA concentrations. However the implicit reduction in adipose tissue fatty acid uptake goes beyond this and shows a maladaptive response with a severely impaired pathway for direct dietary fat storage. This adipose tissue response to obesity may provide the pathophysiological basis for ectopic fat deposition and lipotoxicity.

Show MeSH
Related in: MedlinePlus