SAT038 Dietary Trans-10,cis-12 Conjugated Linoleic Acid Regulates Glucose Levels In Mice With Severe Insulin Resistance: Potential Effects On The Liver Via HNF4α And FOX01

Disclosure: S.M. Lee: None. J.T. Muratalla: None. C.W. Liew: None. J. Cordoba-Chacon: None. Plasma trans-10 cis-12-conjugated linoleic acid CLA (t10c12-CLA) is inversely associated with increased risk of diabetes in humans. In mice, it is well-known that t10c12-CLA induces whole-body insulin resistance due to severe lipodystrophy (loss of whole-body adipose tissue). However, t10c12-CLA-fed mice show normal glucose levels and, t10c12-CLA improved glucose clearance in models with preexisting insulin resistance: Zucker fatty/diabetic rats, obese and insulin resistant Ldlr-/- mice, and diet-induced obese and insulin resistant male mice. In this study, we assessed whether supplementation of t10c12-CLA in a low-fat diet reduces glucose levels in adipocyte-specific insulin receptor knockout (IRFKO) mice, which is a mouse model of congenital lipodystrophy. In addition to lipodystrophy, IRFKO mice show liver steatosis and increased blood glucose levels that are consequences of whole-body insulin resistance and increased hepatic gluconeogenesis. Briefly, 5-6-week-old male and female control and IRFKO mice were fed with a low-fat diet supplemented with 0.8% t10c12-CLA for 5 weeks. In IRFKO mice, dietary t10c12-CLA did not reduce adipose tissue mass. However, dietary t10c12-CLA increased liver steatosis and plasma insulin levels. Surprisingly, dietary t10c12-CLA reduced glucose levels in both male and female IRFKO mice. Also, dietary t10c12-CLA reduced food intake and polydipsia, which were increased in IRFKO mice due to lipodystrophy and hyperglycemia, respectively. A transcriptomic analysis (RNA-seq) of livers of control and IRFKO male mice fed with a t10c12-CLA diet showed that t10c12-CLA reduced the expression of the key gluconeogenic and mitochondrial fatty oxidation genes. Previous studies have suggested that t10c12-CLA reduces the expression of Forkhead box 01 (Fox01) and Hepatocyte nuclear factor 4 alpha (HNF4α). Of note, the livers of t10c12-CLA-fed control and IRFKO male mice showed a downregulation of positive targets of FoxO1 and HNF4α. In addition, livers of t10c12-CLA-fed mice showed reduced total FOXO1 protein levels, and increased phosphorylation of FOXO1 in t10c12-CLA-fed IRFKO mice. These findings suggest that t10c12-CLA could be directly acting on the liver to alter HNF4α and FOXO1-dependent regulation of hepatic fatty acid oxidation and glucose production. These actions may explain why t10c12-CLA-fed mice do not show increased glucose levels and is potentially linked to the inverse association between t10c12-CLA levels and diabetes risk. Presentation: Saturday, June 17, 2023