Enhancing hepatic glycolysis reduces obesity: Differential effects on lipogenesis depend on site of glycolytic modulation

Abstract

Reducing obesity requires an elevation of energy expenditure and/or a suppression of food intake. Here we show that enhancing hepatic glycolysis reduces body weight and adiposity in obese mice. Overexpression of glucokinase or 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is used to increase hepatic glycolysis. Either of the two treatments produces similar increases in rates of fatty acid oxidation in extrahepatic tissues, i.e., skeletal muscle, leading to an elevation of energy expenditure. However, only 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase overexpression causes a suppression of food intake and a decrease in hypothalamic neuropeptide Y expression, contributing to a more pronounced reduction of body weight with this treatment. Furthermore, the two treatments cause differential lipid profiles due to opposite effects on hepatic lipogenesis, associated with distinct phosphorylation states of carbohydrate response element binding protein and AMP-activated protein kinase. The step at which hepatic glycolysis is enhanced dramatically influences overall whole-body energy balance and lipid profiles.

Liver Glucokinase and Lipid Metabolism

“…It is tempting to speculate that glucose taken-up in perivenous liver, both in postprandial and post-absorptive periods, could be directed towards the glycolytic www.intechopen.com and oxidative metabolism and not through the pentose phosphate pathway that would favor lipid biosynthesis. This hypothesis is reinforced by results published by Wu et al (Wu, 2005) in which adenovirus expression of wild-type GK in the liver activate the pentose phosphate pathway, in marked contrast to the overexpression of the kinase domain from PFK-2 that stimulates flux through the glycolytic pathway. Surprisingly, GK-A456V transfected animals showed a marked increase in glucose-6-phosphatase.…”

“…Animal diabetic models linked to obesity, show that GK deficiency in the liver occurs only in the case of obesity, and in severe or long-term forms of the disease. Although hepatic GK expression is different depending on disease stage, some strategies www.intechopen.com based on increasing GK activity in the liver have been tested in some models of high fat diet induced type 2 diabetes & Ferre, 2003 , in obesity models (Wu, 2005& Torres, 2009) and in transgenic mice with hepatic insulin resistance (Okamoto, 2007). All these studies have in common that the increase in hepatic GK activity produces glycaemia normalization.…”

Targeted Overexpression of Inducible 6-Phosphofructo-2-kinase in Adipose Tissue Increases Fat Deposition but Protects against Diet-induced Insulin Resistance and Inflammatory Responses

“…After the feeding regimen, mice were fasted for 4 h before sacrifice for collection of blood and tissue samples (24 -26). Epididymal, mesenteric, and perinephric fat depots were dissected and weighed as visceral fat content (25). After weighing, adipose tissue and liver samples were either fixed and embedded for histological and immunohistochemical analyses or frozen in liquid nitrogen and stored at Ϫ80°C for further analyses.…”

“…Western blots were conducted as described previously (25,26). The levels of iPFK2, Akt1/2, phospho-Akt (Ser-473), NF-B p65, and phospho-p65 (Ser-468) were quantified.…”

“…Mouse primary hepatocytes were isolated as described previously (25,28). To address direct effects of adipocyte factors generated in response to PFKFB3/iPFK2 action, isolated WT hepatocytes were treated with iPFK2-OX-adipocyte-conditioned medium (iPFK2-OX-CM) or GFP-expressing adipocyte-conditioned medium (GFP-CM, control) in M199 medium at a 1:1 ratio for 48 h in the presence or absence of palmitate (250 M) for the last 24 h. Hepatocyte lipid accumulation was analyzed using Oil Red O staining and the colorimetric assay to quantify triglyceride content.…”