Short-Term Overexpression of a Constitutively Active Form of AMP-Activated Protein Kinase in the Liver Leads to Mild Hypoglycemia and Fatty Liver

Abstract

AMP-activated protein kinase (AMPK) is a major therapeutic target for the treatment of diabetes. We investigated the effect of a short-term overexpression of AMPK specifically in the liver by adenovirus-mediated transfer of a gene encoding a constitutively active form of AMPK␣2 (AMPK␣2-CA). Hepatic AMPK␣2-CA expression significantly decreased blood glucose levels and gluconeogenic gene expression. Hepatic expression of AMPK␣2-CA in streptozotocin-induced and ob/ob diabetic mice abolished hyperglycemia and decreased gluconeogenic gene expression. In normal mouse liver, AMPK␣2-CA considerably decreased the refeeding-induced transcriptional activation of genes encoding proteins involved in glycolysis and lipogenesis and their upstream regulators, SREBP-1 (sterol regulatory element-binding protein-1) and ChREBP (carbohydrate response element-binding protein). This resulted in decreases in hepatic glycogen synthesis and circulating lipid levels. Surprisingly, despite the inhibition of hepatic lipogenesis, expression of AMPK␣2-CA led to fatty liver due to the accumulation of lipids released from adipose tissue. The relative scarcity of glucose due to AMPK␣2-CA expression led to an increase in hepatic fatty acid oxidation and ketone bodies production as an alternative source of energy for peripheral tissues. Thus, short-term AMPK activation in the liver reduces blood glucose levels and results in a switch from glucose to fatty acid utilization to supply energy needs.

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

“…Also other aspects of the phenotype seen in the mice overexpressing Il6 are consistent with increased AMPK activation in several organs. Overproduction of AMPK in the liver produced mild hypoglycaemia due to reduced gluconeogenesis, including reduced Pepck expression [49] as also seen in our mice. However, the insulin levels were lower in those mice in contrast to our findings, where they were inappropriately high, supporting the notion of a stimulating effect of IL-6 on the islet beta cells.…”

“…This constellation should also reduce insulin sensitivity in the liver, but this was obviously overcome by the marked hyperinsulinaemia. Interestingly, however, these mice did not develop fatty liver, which has been seen in mice specifically overproducing SOCS3 or AMPK respectively in the liver [49,50]. In our mice, it is likely that the marked reduction in adipose tissue mass and circulating NEFA levels, combined with increased lipid oxidation and AMPK activation in skeletal muscle, prevented this effect.…”

AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

“…Similar to the protective effect against OLZ-induced reductions in the insulin response, co-treatment with AICAR completely protected against OLZ-induced excursions in blood glucose following a pyruvate challenge, however the mechanisms mediating this effect are not clear. Although AICAR activates AMPK and the prolonged activation of this enzyme reduces hepatic gluconeogenic capacity (Foretz et al, 2005), it has recently been shown that AICAR-mediated inhibition of glucose production was intact in liver-specific AMPK knockout mice (Hasenour et al, 2014). AICAR, in addition to increasing ZMP, has also been reported to increase AMP secondary to an inhibition of mitochondrial respiration (Hasenour et al, 2014).…”

“…Published on March 26, 2018as DOI: 10.1124 at ASPET Journals on April 5, 2019 jpet.aspetjournals.org Downloaded from JPET #248393 6 energy-sensing enzyme AMP-activated protein kinase (AMPK). The activation of AMPK in skeletal muscle improves insulin sensitivity (O'Neill et al, 2014;Kjøbsted et al, 2015), stimulates glucose uptake (Jørgensen et al, 2004) and enhances fat oxidation (O'Neill et al, 2014), while AMPK activation in the liver leads to reductions in gluconeogenesis (Foretz et al, 2005). The effects of AICAR in the liver are likely not solely attributable to AMPK as the AICAR-mediated inhibition of glucose production was intact in liver-specific AMPK knockout mice (Hasenour et al, 2014).…”

Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes

“…AMPK may also be regulated through the glycogenbinding domain on the β subunit by the content and structure of intracellular glycogen [9]. When stimulated, AMPK acts to restore cellular energy balance by stimulating ATP-producing pathways (glucose uptake, fatty acid oxidation and mitochondrial biogenesis) [10][11][12][13] and inhibiting ATP-consuming pathways (fatty acid synthesis, glycogen synthesis and protein synthesis) [14][15][16][17].…”