The effect of high fat diet and metformin treatment on liver lipids accumulation and their impact on insulin action

Abstract

We sought to determine whether metformin treatment reverses a high-fat diet (HFD)-induced hepatic insulin resistance (IRes) and to identify lipid intermediates involved in induction of liver IRes. The experiments were conducted on male Wistar rats divided into three groups: 1. Control, 2. fed HFD and 3. fed HFD and treated with metformin. The animals were infused with a [U-13C]palmitate to measure fractional lipid synthesis rate. This allowed for the calculation of fractional synthesis rate of signaling lipids (FSR) through the estimation of their isotopic enrichment. Liver ceramide (Cer), diacylglycerol (DAG) and acyl-carnitine concentration and enrichment were analyzed by LC/MS/MS. The content of proteins involved in lipid metabolism and insulin signaling were analyzed by Western Blot. HFD treatment increased the content and FSR of DAG and Cer in the liver which was accompanied by systemic insulin resistance and inhibition of hepatic insulin signaling pathway under insulin stimulation. Metformin treatment ameliorated systemic insulin resistance and augmented the hepatic insulin signaling cascade. It reduced both the concentration and FSR of Cer, DAG, and increased acyl-carnitine content and the expression of mitochondrial markers. We postulate, that in liver, the insulin sensitizing effect of metformin depends on augmentation of mitochondrial β-oxidation, which protects from hepatic accumulation of both the Cer and DAG and preserves insulin sensitivity under HFD consumption. Moreover, we showed that hepatic content of Cer and DAG corresponds with their respective FSR.

Of mice and men: Is there a future for metformin in the treatment of hepatic steatosis?

“…In HFD‐fed mice, metformin (310 mg/kg/d) reduced liver fat (from 34% to 20%); however, the treated mice had an ~11% reduction in body weight, which may contribute to the decrease in IHTAG content when metformin is given. As well as decreasing IHTAG, it has also been shown that metformin alters intra‐hepatocellular lipid composition, reducing diacylglycerol and ceramide content and increasing unsaturated fatty acids within the livers of metformin‐treated mice compared with untreated mice and in high fat diet (HFD)‐fed rats treated with metformin …”

“…As well as decreasing IHTAG, it has also been shown that metformin alters intra-hepatocellular lipid composition, reducing diacylglycerol and ceramide content and increasing unsaturated fatty acids within the livers of metformin-treated mice compared with untreated mice 28 and in high fat diet (HFD)-fed rats treated with metformin. 30…”

Ceramide Content in Liver Increases Along with Insulin Resistance in Obese Patients

“…In genetically obese Zucker diabetic fatty (ZDF) rats [22] or in mice fed high-fat diet (HFD) [17] no increase in total hepatic ceramide was observed despite the induction of glucose metabolism disorders. However, most studies have shown that HFD leads to an increase in liver ceramide levels, accompanied by a decrease in insulin sensitivity [18][19][20][21][22]. In study performed on C57BL/6N mice fed HFD diet for 14 weeks, a significant increase in C14:0-Cer, C16:0-Cer, C18:0-Cer, C20:0-Cer, and C24:1-Cer was observed [21].…”

“…The mechanism of defects in hepatic insulin-signaling cascade has not been thoroughly understood, but it has been well documented that hepatic insulin resistance is associated with an increased hepatic lipid accumulation [28][29][30]. For many years, the attention of scientists was focused on the participation of triacylglycerols in hepatic insulin resistance, but studies performed on animal have demonstrated that biologically active lipids such as ceramides, can be directly involved in induction of liver metabolic abnormalities [18][19][20][21][22]. However, there are conflicting data regarding the role of ceramide in the induction of hepatic insulin resistance.…”

“…In some works, both short-and long-term feeding with a high fat diet did not lead to an increase of ceramides in the liver, despite the induction of insulin resistance [15][16][17]. However, in most studies performed on animals, ceramide and other lipids content increases along with obesity, high fat diet feeding, or lard oil infusion [18][19][20][21][22], which is usually accompanied by a decrease in insulin sensitivity. However, there is still an unsolved mystery whether hepatic insulin resistance in humans is associated with the accumulation of ceramide in the liver.…”