the fatzo mouse model of type 2 diabetes develops non ...€¦ · the fatzo mouse model of type 2...
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The FATZO Mouse Model of Type 2 Diabetes Develops Non-Alcoholic Fatty Liver Disease (NAFLD)
Van Jackson1, and Sandeep Sinha2, 1PreClinOmics Inc., a Crown Bioscience Company, Indianapolis, IN; 2Crown Bioscience Inc., Santa Clara, CA
INTRODUCTION RESULTS
Non-alcoholic fatty liver disease (NAFLD) develops at a higher rate in obese, Type 2 diabetic individuals. There are no approved pharmaco-therapies for the treatment of NAFLD or of its exacerbated form called non-alcoholic fatty liver disease (NASH). The FATZO mouse has been developed at PreClinOmics Inc., a Crown Bioscience Company, as a model of Type 2 diabetes, that spontaneously develops obesity, hyperglycemia, glucose intolerance, and insulin resistance. The purpose of this investigation was to characterize the FATZO mouse fed a Western diet supplemented with fructose in the drinking water as a potential model for NAFLD and NASH.
METHODS
FATZO mice (n=104) at 8 weeks of age were randomized based on body weight and glucose levels into 2 groups of 48 animals each. The remaining eight animals were used to establish baseline parameters for the remainder of the study. One group was placed on a Western diet (Research Diets D12079B diet) + 5% fructose in their drinking water. The other group remained on regular Purina 5008 diet. Each month, 8 animals from each group were terminated and blood was collected via cardiac puncture for the plasma analysis of glucose, insulin, AST, ALT, cholesterol, and triglycerides. Livers were collected, weighed, and then split with one part fixed in 10% buffered formalin and the other part snap frozen in liquid nitrogen for histology and liver triglyceride determination. All data are presented as the Mean±SEM, n=8.
SUMMARY
• The data demonstrate that the FATZO mouse develops NAFLD after 2 months on a Western diet supplemented with 5% fructose, which is maintained for up to 5 months.
• At 4 months, NASH histological scoring demonstrates steatosis, inflammation, ballooning, and early signs of fibrosis. • Further research is needed to determine if the FATZO mouse will develop NASH and eventually hepatic cellular carcinoma.
NASH Histology Scoring Animal ID Steatosis Lob Inflam Balloon Degen Fibrosis 550345033 1 0 1 0
5008
550345034 2 1 3 0 550345035 1 0 1 0 550345036 1 0 1 0 550345037 2 0 2 0 550345038 2 1 3 1 550345039 1 1 1 0 550345040 1 0 0 0
Western
550345081 2 1 4 0 550345082 2 1 4 0 550345083 2 1 4 0 550345084 2 1 4 0 550345085 2 2 4 1 550345086 2 1 4 1 550345087 2 1 4 1 550345088 2 2 4 1
4 Month Histology NASH Scoring
200 µm 200 µm
Lipid Ballooning
5008 Diet Western Diet
RESULTS
0 4 8 12 160
100
200
300
400
Weeks on Diet
ALT
(U/L
)
5008Western+Fructose
Mean–SEM, n=8
0 4 8 12 1630
35
40
45
50
Weeks on Diet
Bod
yW
eigh
t(g) 5008
Western+Fructose
Mean–SEM, n=8
0 4 8 12 160
100
200
300
400
Weeks on Diet
Cho
lest
erol
(mg/
dL)
5008Western+Fructose
Mean–SEM, n=8
0 4 8 12 160
100
200
300
Weeks on Diet
Trig
lyce
rides
(mg/
dL)
5008Western+Fructose
Mean–SEM, n=8
0 4 8 12 160
100
200
300
400
500
Weeks on Diet
AST
(U/L
)
5008Western+Fructose
Mean–SEM, n=8
0 4 8 12 1620
25
30
35
40
Weeks on Diet
%B
ody
Fat
5008Western+Fructose
Mean–SEM, n=8
0 4 8 12 160
2
4
6
Weeks on Diet
Live
rWei
ght(
g) 5008Western+Fructose
Mean–SEM, n=8
5008 Western+Fructose0
20
40
60
LiverTriglycerides
(mg/gtissue)
Mean–SEM, n=8