Mechanistic insights revealed by lipid profiling in monogenic insulin resistance syndromes.
BACKGROUND
Evidence from several recent metabolomic studies suggests that increased concentrations of triacylglycerols with shorter (14-16 carbon atoms), saturated fatty acids are associated with insulin resistance and the risk of type 2 diabetes. Although causality cannot be inferred from association studies, patients in whom the primary cause of insulin resistance can be genetically defined offer unique opportunities to address this challenge.


METHODS
We compared metabolite profiles in patients with congenital lipodystrophy or loss-of-function insulin resistance (INSR gene) mutations with healthy controls.


RESULTS
The absence of significant differences in triacylglycerol species in the INSR group suggest that changes previously observed in epidemiological studies are not purely a consequence of insulin resistance. The presence of triacylglycerols with lower carbon numbers and high saturation in patients with lipodystrophy suggests that these metabolite changes may be associated with primary adipose tissue dysfunction. The observed pattern of triacylglycerol species is indicative of increased de novo lipogenesis in the liver. To test this we investigated the distribution of these triacylglycerols in lipoprotein fractions using size exclusion chromatography prior to mass spectrometry. This associated these triacylglycerols with very low-density lipoprotein particles, and hence release of triacylglycerols into the blood from the liver. To test further the hepatic origin of these triacylglycerols we induced de novo lipogenesis in the mouse, comparing ob/ob and wild-type mice on a chow or high fat diet, confirming that de novo lipogenesis induced an increase in relatively shorter, more saturated fatty acids.


CONCLUSIONS
Overall, these studies highlight hepatic de novo lipogenesis in the pathogenesis of metabolic dyslipidaemia in states where energy intake exceeds the capacity of adipose tissue.
MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK.
Michael
M
Eiden
MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK.
Albert
A
Koulman
Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Mensud
M
Hatunic
MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK ; Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, Cambridge, UK.
James A
JA
West
Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, Cambridge, UK.
Steven
S
Murfitt
MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK.
Michael
M
Osei
Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Claire
C
Adams
MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK ; Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, Cambridge, UK.
Xinzhu
X
Wang
Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, Cambridge, UK.
Yajing
Y
Chu
MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK.
Luke
L
Marney
MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK ; Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, Cambridge, UK.
Lee D
LD
Roberts
Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Stephen
S
O'Rahilly
Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Robert K
RK
Semple
Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
David B
DB
Savage
MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK ; Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, Cambridge, UK.
Julian L
JL
Griffin
D000293:Adolescent; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D059305:Diet, High-Fat; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D034904:Lamin Type A / Q000235:genetics; D008055:Lipids / Q000097:blood*; D052497:Lipodystrophy, Congenital Generalized / Q000097:blood* / Q000235:genetics; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics; D055815:Young Adult
D015703:Antigens, CD; D034904:Lamin Type A; D008055:Lipids; D047495:PPAR gamma; C435941:INSR protein, human; D011972:Receptor, Insulin