Lipin Deficiency Impairs Diurnal Metabolic Fuel Switching

Abstract

Fatty liver is a common feature of both obesity and lipodystrophy, reflecting compromised adipose tissue function. The lipin-deficient fatty liver dystrophy (fld) mouse is an exception, as there is lipodystrophy without a fatty liver. Using a combination of indirect calorimetry and stableisotope flux phenotyping, we determined that fld mice exhibit abnormal fuel utilization throughout the diurnal cycle, with increased glucose oxidation near the end of the fasting period and increased fatty acid oxidation during the feeding period. The mechanisms underlying these alterations include a twofold increase compared with wild-type mice in tissue glycogen storage during the fed state, a 40% reduction in hepatic glucose production in the fasted state, and a 27-fold increase in de novo fatty acid synthesis in liver during the fed state. Thus, the inability to store energy in adipose tissue in the fld mouse leads to a compensatory increase in glycogen storage for use during the fasting period and reliance upon hepatic fatty acid synthesis to provide fuel for peripheral tissues during the fed state. The increase in hepatic fatty acid synthesis and peripheral utilization provides a potential mechanism to ameliorate fatty liver in the fld that would otherwise occur as a consequence of adipose tissue dysfunction. Diabetes 55:3429 -3438, 2006

Relationship of glucose and oleate metabolism to cardiac function in lipin-1 deficient (fld) mice

“…Surprisingly, cardiac function in the perfused fl d hearts was not signifi cantly different from the control hearts even though the fl d hearts were smaller. This suggests that the cardiac dysfunction we observed in fl d mice in vivo may be related to the systemic changes stemming from global lipin-1 deficiency, which can be described as a combination of the absence of adipose tissue, the corresponding decrease in adipokine secretion, whole-body insulin resistance, aberrant changes in the circadian rhythm of whole-body metabolism ( 16,66,67 ), and higher workload in vivo compared with ex vivo. We also found decreased circulating TG levels in fl d mice ( Table 2 ), which could affect the availability of substrate for cardiac work.…”

“…However, lipin-1 is required for promoting transcriptional regulation of PPAR ␣ and its target genes in the livers of fl d mice, and there does not appear to be compensation of lipin-1 transcriptional coactivator function by lipin-2 or lipin-3 in the liver ( 23 ), in spite of lipin-2 being highly expressed in hepatocytes ( 14,25 ). Indeed, the changes in mRNA levels of PPAR ␣ , PGC-1 ␣ , and a subset of their targets could be a compensatory response in vivo to the aberrant fuel utilization of fl d mice in the diurnal cycle ( 67 ). Furthermore, there was increased activation of PDH as shown by decreased phosphorylated PDH, which refl ects the inability of the fl d mice to utilize FAs to the same extent as control mice in the fasted state ( 70 ).…”

“…Although we did not see differences in glucose oxidation, we found increased PDH activation. Other studies on fl d mice show changes in energy partitioning in vivo, which could aberrantly affect cardiac function ( 66,67 ).…”

Glucocorticoids and cyclic AMP selectively increase hepatic lipin-1 expression, and insulin acts antagonistically

“…The coregulation of lipin-1 expression and the physical interactions of lipin-1 with PGC-1a and PPARa (27) could help to modulate and integrate gluconeogenesis with the increased capacity for hepatic TAG synthesis and b-oxidation in starvation and diabetes. In this respect, it may be significant that the livers of fld mice show a 40% decrease in hepatic glucose production in fasting (48).…”

Enriched Environment-induced Maternal Weight Loss Reprograms Metabolic Gene Expression in Mouse Offspring

“…5D). Lpin1 expression reduces triglyceride release from liver, and its deficiency is associated with insulin resistance and fatty liver (33,34). Interestingly, expression of Lpin1 was significantly increased (Fig.…”