Energy metabolism couples hepatocyte integrin-linked kinase to liver glucoregulation and postabsorptive responses of mice in an age-dependent manner

Abstract

Integrin-linked kinase (ILK) is a critical intracellular signaling node for integrin receptors. Its role in liver development is complex, as ILK deletion at E10.5 (before hepatocyte differentiation) results in biochemical and morphological differences that resolve as mice age. Nevertheless, mice with ILK depleted specifically in hepatocytes are protected from the hepatic insulin resistance during obesity. Despite the potential importance of hepatocyte ILK to metabolic health, it is unknown how ILK controls hepatic metabolism or glucoregulation. The present study tested the role of ILK in hepatic metabolism and glucoregulation by deleting it specifically in hepatocytes, using a cre-lox system that begins expression at E15.5 (after initiation of hepatocyte differentiation). These mice develop the most severe morphological and glucoregulatory abnormalities at 6 wk, but these gradually resolve with age. After identifying when the deletion of ILK caused a severe metabolic phenotype, in depth studies were performed at this time point to define the metabolic programs that coordinate control of glucoregulation that are regulated by ILK. We show that 6-wk-old ILK-deficient mice have higher glucose tolerance and decreased net glycogen synthesis. Additionally, ILK was shown to be necessary for transcription of mitochondrial-related genes, oxidative metabolism, and maintenance of cellular energy status. Thus, ILK is required for maintaining hepatic transcriptional and metabolic programs that sustain oxidative metabolism, which are required for hepatic maintenance of glucose homeostasis.

EGFR-mediated activation of adipose tissue macrophages promotes obesity and insulin resistance

“…We assessed energy balance by indirect calorimetry experiments using a Promethion metabolic cage system in MΦ EGFR −/− mice and littermate WT controls with chow food and with HFD for 4 weeks through Vanderbilt MMPC 17 . Body composition was determined by NMR (Bruker Minispec).…”

“…Mice were individually placed in home-cages in a 12 h light/dark cycle, temperature/humidity-controlled dedicated room located in the Vanderbilt MMPC (RRID: SCIR_021939). Energy expenditure measures were obtained by indirect calorimetry (Promethion, Sable Systems, Las Vegas, NV) 17 . The calorimetry system consists of home cages with bedding equipped with water bottles and food hoppers connected to load cells for food and water intake monitoring.…”

Disrupted liver oxidative metabolism in glycine N-methyltransferase-deficient mice is mitigated by dietary methionine restriction

“…Liver samples were sent to Human Metabolome Technologies America, Inc. (Boston, MA) for targeted and untargeted metabolite quantification as previously described [ [38] , [39] , [40] , [41] ]. Phospholipids, diacylglycerides, and triacylglycerides were measured as previously outlined [ 42 ]. Glycogen was determined as previously described [ 43 ].…”

Potential positive and negative consequences of ZnT8 inhibition

“…This is consistent with the absence of differences in gene expression comparing WT and Slc30a8 adult mouse islets using microarrays (data not shown). Resolution of gene expression changes with aging have been reported in other KO mouse models (Trefts et al 2019). While G6PC2 opposes the action of the glucose sensor glucokinase (O' Brien 2013), this increased expression is unlikely to contribute to the altered kinetics of insulin secretion or clearance in 4-week-old Slc30a8 KO mice (Fig.…”