TY - JOUR
T1 - Molecular mechanisms underlying fasting modulated liver insulin sensitivity and metabolism in male lipodystrophic Bscl2/seipin-deficient mice
AU - Chen, Weiqin
AU - Zhou, Hongyi
AU - Saha, Pradip
AU - Li, Luge
AU - Chan, Lawrence
N1 - Publisher Copyright:
Copyright © 2014 by the Endocrine Society.
PY - 2014/11/1
Y1 - 2014/11/1
N2 - Bscl2-/- mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatomegly, hepatic steatosis, and insulin resistance. The mechanisms that underlie hepatic steatosis and insulin resistance in Bscl2-/- mice are poorly understood. To address this issue, we performed hyperinsuline-mic-euglycemic clamp on Bscl2-/- and wild-type mice after an overnight (16-h) fast, and found that Bscl2-/- actually displayed increased hepatic insulin sensitivity. Interestingly, liver in Bscl2-/- mice after a short term (4-h) fast had impaired acute insulin signaling, a defect that disappeared after a 16-hour fast. Notably, fasting-dependent hepatic insulin signaling in Bscl2-/- mice was not associated with liver diacylglyceride and ceramide contents, but could be attributable in part to the expression of hepatic insulin signaling receptor and substrates. Meanwhile, increased de novo lipogenesis and decreased β-oxidation led to severe hepatic steatosis in fed or short-fasted Bscl2-/- mice whereas liver lipid accumulation and metabolism in Bscl2-/- mice was markedly affected by prolonged fasting. Furthermore, mice with liver-specific inactivation of Bscl2 manifested no hepatic steatosis even under high-fat diet, suggesting Bscl2 does not play a cell autonomous role in regulating liver lipid homeostasis. Overall, our results offered new insights into the metabolic adaptations of liver in response to fasting and uncovered a novel fasting-dependent regulation of hepatic insulin signaling in a mouse model of human BSCL2.
AB - Bscl2-/- mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatomegly, hepatic steatosis, and insulin resistance. The mechanisms that underlie hepatic steatosis and insulin resistance in Bscl2-/- mice are poorly understood. To address this issue, we performed hyperinsuline-mic-euglycemic clamp on Bscl2-/- and wild-type mice after an overnight (16-h) fast, and found that Bscl2-/- actually displayed increased hepatic insulin sensitivity. Interestingly, liver in Bscl2-/- mice after a short term (4-h) fast had impaired acute insulin signaling, a defect that disappeared after a 16-hour fast. Notably, fasting-dependent hepatic insulin signaling in Bscl2-/- mice was not associated with liver diacylglyceride and ceramide contents, but could be attributable in part to the expression of hepatic insulin signaling receptor and substrates. Meanwhile, increased de novo lipogenesis and decreased β-oxidation led to severe hepatic steatosis in fed or short-fasted Bscl2-/- mice whereas liver lipid accumulation and metabolism in Bscl2-/- mice was markedly affected by prolonged fasting. Furthermore, mice with liver-specific inactivation of Bscl2 manifested no hepatic steatosis even under high-fat diet, suggesting Bscl2 does not play a cell autonomous role in regulating liver lipid homeostasis. Overall, our results offered new insights into the metabolic adaptations of liver in response to fasting and uncovered a novel fasting-dependent regulation of hepatic insulin signaling in a mouse model of human BSCL2.
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U2 - 10.1210/en.2014-1292
DO - 10.1210/en.2014-1292
M3 - Article
C2 - 25093462
AN - SCOPUS:84908052440
SN - 0013-7227
VL - 155
SP - 4215
EP - 4225
JO - Endocrinology
JF - Endocrinology
IS - 11
ER -