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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