Glp-1 analog, liraglutide, ameliorates hepatic steatosis and cardiac hypertrophy in C57BL/6J mice fed a Western diet

Abstract

The aims of this study were designed to determine whether liraglutide, a long-acting glucagon-like peptide, could reverse the adverse effects of a diet high in fat that also contained trans-fat and high-fructose corn syrup (ALIOS diet). Specifically, we examined whether treatment with liraglutide could reduce hepatic insulin resistance and steatosis as well as improve cardiac function. Male C57BL/6J mice were pair fed or fed ad libitum either standard chow or the ALIOS diet. After 8 wk the mice were further subdivided and received daily injections of either liraglutide or saline for 4 wk. Hyperinsulinemic-euglycemic clamp studies were performed after 6 wk, revealing hepatic insulin resistance. Glucose tolerance and insulin resistance tests were performed at 8 and 12 wk prior to and following liraglutide treatment. Liver pathology, cardiac measurements, blood chemistry, and RNA and protein analyses were performed. Clamp studies revealed hepatic insulin resistance after 6 wk of ALIOS diet. Liraglutide reduced visceral adiposity and liver weight (P < 0.001). As expected, liraglutide improved glucose and insulin tolerance. Liraglutide improved hypertension (P < 0.05) and reduced cardiac hypertrophy. Surprisingly, liver from liraglutide-treated mice had significantly higher levels of fatty acid binding protein, acyl-CoA oxidase II, very long-chain acyl-CoA dehydrogenase, and microsomal triglyceride transfer protein. We conclude that liraglutide reduces the harmful effects of an ALIOS diet by improving insulin sensitivity and by reducing lipid accumulation in liver through multiple mechanisms including, transport, and increase β-oxidation.

Mechanisms in endocrinology: Non-alcoholic fatty liver disease in common endocrine disorders

“…The administration of GLP agonists reduces hepatic steatosis and decreases serum glucose, IR and markers of oxidative stress in rodent models (95,96), decreasing the expression of lipogenic genes including SREBP-1c and SCD1 and increasing those involved in b-oxidation including PPARa (95,97).…”

Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as Measured by Magnetic Resonance in Patients With Type 2 Diabetes: A Randomized Trial

“…Further, GLP-1 agonists may decrease liver fat by increasing fatty acid uptake and VLDL transport (10) and stimulating hepatic lipid b-oxidation (11,12), improving hepatic insulin sensitivity (10) while also reducing hepatic lipogenesis via activation of the AMPK pathway (13).…”

Gut hormones such as amylin and GLP-1 in the control of eating and energy expenditure

“…Although the GLP-1 antagonist exendin-9 has been reported to increase eating under some conditions, 26 a specific effect of exendin-9 on meal size has not been observed consistently and may be weak (for example, Ruttimann et al, 27 Steinert et al 28 and Melhorn et al 29 ). Finally, chronic administration of amylin, GLP-1 or their analogs has been shown to reduce body weight by reducing food intake, [30][31][32] and at least in the case of amylin, this was associated with decreased meal sizes over extended time periods. 30 …”