Dissipating Excess Energy Stored in the Liver Is a Potential Treatment Strategy for Diabetes Associated With Obesity

Abstract

For examining whether dissipating excess energy in the liver is a possible therapeutic approach to high-fat diet-induced metabolic disorders, uncoupling protein-1 (UCP1) was expressed in murine liver using adenoviral vectors in mice with high-fat diet-induced diabetes and obesity, and in standard diet-fed lean mice. Once diabetes with obesity developed, hepatic UCP1 expression increased energy expenditure, decreased body weight, and reduced fat in the liver and adipose tissues, resulting in markedly improved insulin resistance and, thus, diabetes and dyslipidemia. Decreased expressions of enzymes for lipid synthesis and glucose production and activation of AMP-activated kinase in the liver seem to contribute to these improvements. Hepatic UCP1 expression also reversed high-fat diet-induced hyperphagia and hypothalamic leptin resistance, as well as insulin resistance in muscle. In contrast, intriguingly, in standard diet-fed lean mice, hepatic UCP1 expression did not significantly affect energy expenditure or hepatic ATP contents. Furthermore, no alterations in blood glucose levels, body weight, or adiposity were observed. These findings suggest that ectopic UCP1 in the liver dissipates surplus energy without affecting required energy and exerts minimal metabolic effects in lean mice. Thus, enhanced UCP expression in the liver is a new potential therapeutic target for the metabolic syndrome. Diabetes 54:322-332, 2005 A n explosive increase in the number of diabetic patients, which has become a major public health concern in most industrialized countries in recent decades (1), is mainly the result of excess energy intake and physical inactivity. When food intake chronically exceeds metabolic needs, efficient metabolism causes excess energy storage and results in obesity, a common condition associated with diabetes, hyperlipidemia, and premature heart disease. Excess energy in cells lowers the response to insulin, namely insulin resistance. However, the major treatment modalities for diabetes, including insulin injection and oral sulfonylureas, aim at lowering blood glucose levels by driving glucose into cells in peripheral tissues such as muscle and fat. This further exacerbates insulin resistance when energy intake is in excess, resulting in a vicious cycle. Therefore, novel therapies that promote increased energy expenditure are needed.Inefficient metabolism, such as the generation of heat instead of ATP, is a potential treatment strategy for type 2 diabetes associated with obesity. Uncoupling proteins (UCPs) were discovered members of the mitochondrial inner membrane carrier family. These proteins leak protons into the mitochondrial matrix, dissipating energy as heat rather than allowing it to be captured in ATP (2). UCP1 (thermogenin) was originally identified in brown adipose tissue and demonstrated to mediate nonshivering thermogenesis. UCP1 plays an important role in mediating cold exposure-induced thermogenesis (3) and is also a likely regulator of diet-induced thermogenesis (4).Several laboratories have r...

Liver mitochondrial properties from the obesity-resistant Lou/C rat

“…15 Hepatic mitochondrial adaptations are particularly interesting since dissipating energy stored in the liver has been suggested as a potential treatment strategy for diabetes associated with obesity. 46 Even though, in the present study, we cannot conclude that the enhanced free radical generation by liver mitochondria of Lou/C rats ( Figure 1) was entirely responsible for mitochondrial adaptations, a recent study suggested that oxidative stress provided by treatment with H 2 O 2 induced depolymerization of microtubules and this event is one of the molecular events involved in the increase in mitochondrial mass upon treatment of human cells with H 2 O 2 . 47 On the basis of a greater capacity for reoxidizing FADH 2 evidenced with G/M/S and octanoylcarnitine, we propose that the enhanced liver mitochondrial H 2 O 2 production in Lou/C rats was due to increases in reverse electron flow through the respiratory-chain complex I and to higher medium-chain acyl-CoA dehydrogenase activity.…”

“…These hepatic mitochondrial characteristics may be of particular interest if we take into account that (1) liver fat accumulation is one of the detrimental events involved in the development of insulin resistance and type 2 diabetes 13 and (2) dissipating excess energy in the liver (mitochondrial uncoupling) is a possible therapeutic approach to high-fat diet-induced metabolic disorders. 46 Such liver adaptations could probably explain the higher insulin sensitivity displayed by Lou/C rats (Couturier K, unpublished data) and the ability of this strain to resist fat accretion and insulin resistance with aging 4 or high-fat diet 2,15 in spite of a strong preference for fat. 5,8,15 …”

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

“…Furthermore, expression of ectopic UCP1 resulted in reduced expression of genes characteristic of differentiated energy-storing adipocytes, such as peroxisome proliferator-activated receptor gamma (PPARc) and aP2 , in analogy with the induction of ''fat burning adipocytes'' in response to leptin treatment in rats (Zhou et al 1999). In accordance, mitochondrial uncoupling in adipocytes in vitro led to lower intracellular ATP concentrations (Yamada et al 2006;Si et al 2009), up-regulation of glycolysis and mitochondrial biogenesis, and down-regulation of energyconsuming pathways such as fatty acid synthesis (Rossmeisl et al 2000;Si et al 2009;Senocak et al 2007), while lactate production was increased (Rossmeisl et al 2000; ) N D Decreased (Ishigaki et al 2005) Mitochondrial biogenesis and/or content Increased (Rossmeisl et al 2002) Content decreased (Han et al 2004) N D Mitochondrial ROS production ND Reduced (Keipert et al 2010) N D Cellular ATP levels Decreased Yamada et al 2006); increased AMP/ATP ratio Unchanged (Li et al 2000) or decreased (Li et al 2000;Couplan et al 2002;Han et al 2004 Rossmeisl et al, unpublished) suggested an upregulation of lipid catabolism in SM of high-fat diet-fed mice in response to the transgenic UCP1 expression in WAT, which is also associated with hypolipidemic effects, especially under fasted conditions. The effect of UCP1 expression on SM phenotype was studied in detail by Couplan et al (2002), who reported a fiber type switch from fast glycolytic fibers to slow oxidative fibers in gastrocnemius and plantaris muscle accompanied by a reduced muscle mass.…”

“…Liver Ishigaki et al (2005), using an adenoviral vector, induced a transient UCP1 gene expression in the liver of mice rendered obese and insulin resistant by prior feeding of a highfat diet. UCP1 content in liver mitochondria peaked at 3-7 days after the adenovirus injection, followed by a decline in the expression.…”

“…Although obesity resistant, the aP2-Ucp1 mice exhibit BAT atrophy associated with decreased norepinephrineinduced respiration at the whole-body level, cold-sensitivity of homozygous (but not heterozygous) transgenic Energy intake Cumulative energy intake decreased or unchanged (Kopecky et al 1996a;Stefl et al 1998) Increased (Couplan et al 2002;Klaus et al 2005) Reduced per animal on HFD (Ishigaki et al 2005) Body temperature Reduced in homozygous mice (Stefl et al 1998) Increased (Gates et al 2007) Unchanged (Li et al 2000) Unchanged (Ishigaki et al 2005) Reduced in cold (Klaus et al 2005) High-fat diet-induced obesity…”