A novel aminosterol reverses diabetes and fatty liver disease in obese mice.
OBJECTIVE
Non-alcoholic fatty liver disease (NAFLD) is common in obesity. However, weight reduction alone does not prevent the development or progression of NAFLD. Since NAFLD is associated with insulin resistance and diabetes, we hypothesized that improvement of these factors would reverse obesity-related NAFLD.


METHODS
We examined the effects of an aminosterol, 1436, on glucose, lipids and liver metabolism in Lep(ob/ob) mice, a model of obesity, severe insulin resistance, diabetes, hyperlipidemia and hepatic steatosis.


RESULTS
1436 decreased body weight, specifically fat content, by inhibiting food intake and increasing energy expenditure. In contrast to weight loss from food restriction, this aminosterol specifically lowered circulating lipids, reversed hepatic steatosis and normalized alanine aminotransferase level. 1436 decreased glucose, increased adiponectin and enhanced insulin action in liver. These changes culminated in inhibition of hepatic triglyceride synthesis and increased fatty acid oxidation. Gene expression studies confirmed a reduction in lipogenic enzymes in liver, and elevation of enzymes involved in lipid catabolism.


CONCLUSIONS
These results demonstrate that 1436 is an effective treatment for insulin resistance and hepatic steatosis in Lep(ob/ob) mice, by decreasing hepatic lipid synthesis and stimulating lipolysis. In contrast, weight loss from food restriction has no substantial effect on insulin resistance, lipids and hepatic steatosis.
Takahashi
Nobuhiko
N
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Qi
Yong
Y
Patel
Hiral R
HR
Ahima
Rexford S
RS
D000818:Animals; D001483:Base Sequence; D001835:Body Weight / Q000187:drug effects; D002777:Cholestanols / Q000627:therapeutic use*; D048909:Diabetes Complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D002777:Cholestanols; D012333:RNA, Messenger; C117498:aminosterol 1436