Loss of stearoyl-CoA desaturase-1 improves insulin sensitivity in lean mice but worsens diabetes in leptin-deficient obese mice.
The lipogenic gene stearoyl-CoA desaturase (SCD)1 appears to be a promising new target for obesity-related diabetes, as mice deficient in this enzyme are resistant to diet- and leptin deficiency-induced obesity. The BTBR mouse strain replicates many features of insulin resistance found in humans with excess visceral adiposity. Using the hyperinsulinemic-euglycemic clamp technique, we determined that insulin sensitivity was improved in heart, soleus muscle, adipose tissue, and liver of BTBR SCD1-deficient mice. We next determined whether SCD1 deficiency could prevent diabetes in leptin-deficient BTBR mice. Loss of SCD1 in leptin(ob/ob) mice unexpectedly accelerated the progression to severe diabetes; 6-week fasting glucose increased approximately 70%. In response to a glucose challenge, Scd1(-/-) leptin(ob/ob) mice had insufficient insulin secretion, resulting in glucose intolerance. A morphologically distinct class of islets isolated from the Scd1(-/-) leptin(ob/ob) mice had reduced insulin content and increased triglycerides, free fatty acids, esterified cholesterol, and free cholesterol and also a much higher content of saturated fatty acids. We believe the accumulation of lipid is due to an upregulation of lipoprotein lipase (20-fold) and Cd36 (167-fold) and downregulation of lipid oxidation genes in this class of islets. Therefore, although loss of Scd1 has beneficial effects on adiposity, this benefit may come at the expense of beta-cells, resulting in an increased risk of diabetes.
Flowers
Jessica B
JB
Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 537606, USA.
Rabaglia
Mary E
ME
Schueler
Kathryn L
KL
Flowers
Matthew T
MT
Lan
Hong
H
Keller
Mark P
MP
Ntambi
James M
JM
Attie
Alan D
AD
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D020738:Leptin / Q000172:deficiency* / Q000235:genetics; D008071:Lipoprotein Lipase / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D013230:Stearoyl-CoA Desaturase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013851:Thinness
D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D013230:Stearoyl-CoA Desaturase; D008071:Lipoprotein Lipase