J Korean Diabetes Assoc.  2007 Jan;31(1):63-74. 10.4093/jkda.2007.31.1.63.

Prevention of Diabetes by Fenofibrate in OLETF Rats: Hepatic Mechanism for Reducing Visceral Adiposity

• Lee HJ
• Park MK
• Lee KI
• An YJ
• Kim JM
• Park JY
• Han Y
• Hong SH
• Choi SS
• Yoo YH
• Suh JD
• Kim DK

• KMID: 2008097
• DOI: http://doi.org/10.4093/jkda.2007.31.1.63

Abstract

BACKGROUND: The aim of this study is to evaluate the hepatic mechanism of fenofibrate that has the diabetes protective action in rats.
METHODS
We chose OLETF rats and divided them into three groups. Fenofibrate (DF) group was fed with diet and fenofibrate (300 mg/kg/day). Paired feeding (Dd) group and free diet (DD) group were fed with diet. After 36 weeks of treatment, all the rats were sacrificed.
RESULTS
The fasting blood glucose level of DF group (8.5 +/- 0.9 mmol/L) showed normal. The fasting blood glucose level of Dd group (22.4 +/- 3.0 mmol/L) and DD group (16.9 +/- 3.7 mmol/L) showed significantly increased than that of DF group (P < 0.01, respectively). The body weight, visceral adipose tissue and subcutaneous adipose tissue of DF group were significantly decreased compared to those of Dd and DD groups (P < 0.01, P < 0.05, P < 0.05). DF group showed significantly increased state-3 respiration rate, ATP synthetic activity, state-4 respiration rate and their blood beta-keton body levels than those of control groups (P < 0.01, respectively). DF group showed normal morphology of hepatocytes but DD and Dd groups showed hepatic steatosis with mitochondrial swellings.
CONCLUSION
Chronic fenofibrate treatment prevents the development of diabetes in OLETF rats with inhibiting gain of body weight and abdominal adiposity. The hepatic mechanism for reducing visceral adiposity is that fenofibrate leads to increasing oxidative phosphorylation, uncoupling and ketogenesis as well as increasing beta-oxidation of fatty acids. Moreover, fenofibrate treatment prevents the development of hepatic steatosis.

Keyword

Adiposity; Insulin resistance; PPAR alpha; Weight loss

MeSH Terms

Adenosine Triphosphate
Adiposity*
Animals
Blood Glucose
Body Weight
Diet
Fasting
Fatty Acids
Fenofibrate*
Hepatocytes
Insulin Resistance
Intra-Abdominal Fat
Mitochondrial Swelling
Oxidative Phosphorylation
PPAR alpha
Rats
Rats, Inbred OLETF*
Respiratory Rate
Subcutaneous Fat
Weight Loss
Adenosine Triphosphate
Blood Glucose
Fatty Acids
Fenofibrate
PPAR alpha

Figure

• 

  Fig. 1 The changes of body weight during the entire experiment. All groups showed the increasing tendency of body weight. The weight gain of fenofibrate group is significantly decreased than that of paired feed group and free diet group. *P < 0.0001, versus paired feed group or free diet group, respectively.

• 

  Fig. 2 Light microscopic findings of the liver in fenofibrate treated group and control groups. H&E stain, original magnification ×200. A, The liver of DF group shows normal morphology. The hepatocytes have increased amount of eosinophilic cytoplasm. However, there is no evidence of hepatitis on entire sections of all cases; B, The liver of Dd group shows fatty change of the hepatocytes; C, The liver of DD group shows marked fatty change of the hepatocytes. This fatty change is severer than that of Dd group.

• 

  Fig. 3 Electron microscopical findings of the hepatocyte in DD and DF groups. A, DD group. Most mitochondria (M) are swollen. Their cristae show varying degrees of disorientation, shortening and reduction in numbers. Lipid droplets (L) are large, and sometimes aggregated (two lipid droplets in the upper left corner). A close contact between the lipid droplet and mitochondria is demonstrated (arrows); B, Fenofibrate group. Most mitochondria appeared normal and only few small lipid droplets were scattered in the cytoplasm. (Bar, 2 µM. N: nucleus).

• 

  Fig. 4 Oxygram of isolated mitochondria from the liver in each group of OLETF rats. In fenofibrate group, the oxygen consumption was sharply increased after addition of ADP (state-3 respiration) but this change was not observed in paired feeding and free diet groups. This meant that both group had marked deteriorations of ADP phosphorylation in their mitochondria. The state-3 respiration was terminated when oligomycin, the inhibitor of oxidative phosphorylation, was added. After that uncoupling process (the state-4 respiration) was induced. The state-4 respiration also decreased in both groups than in fenofibrate treated group.

• 

  Fig. 5 The summary of possible hepatic mechanisms for prevention of diabetes by fenofibrate in OLETF rat. Fenofibrate reduces fat burden on liver via increasing β-oxidation of fatty acid and promoting catabolism of its metabolites at multiple subsidiary sites, where oxidative phosphorylation, uncoupling and ketogenesis are increased. Fenofibrate also prevents hepatocyte injury, such as mitochondrial damage (ballooning) and steatosis. The changes of adipocytokines (adiponectin and leptin) induced by fenofibrate also do beneficial actions on fat burden and injury of the liver. (The findings in this study were presented as bold character) mit, mitochondria, BW, body weight

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