Rosiglitazone Requires Hepatocyte PPARγ Expression to Promote Steatosis in Male Mice With Diet-Induced Obesity

Abstract

Thiazolidinediones (TZD) are peroxisome proliferator-activated receptor γ (PPARγ) agonists that may reduce hepatic steatosis through their effects in adipose tissue and therefore have been assessed as potential therapies to treat nonalcoholic fatty liver disease (NAFLD) in humans. However, some studies suggest that expression and activation of hepatocyte PPARγ promotes steatosis and that would limit the benefits of TZD as a NAFLD therapy. To further explore this possibility, we examined the impact of short-term rosiglitazone maleate treatment after the development of moderate or severe diet-induced obesity, in both control and adult-onset hepatocyte-specific PPARγ knockout (PpargΔHep) mice. Independent of the level of obesity and hepatic PPARγ expression, the TZD treatment enhanced insulin sensitivity, associated with an increase in white adipose tissue (WAT) fat accumulation, consistent with clinical observations. However, TZD treatment increased hepatic triglyceride content only in control mice with severe obesity. Under these conditions, PpargΔHep reduced diet-induced steatosis and prevented the steatogenic effects of short-term TZD treatment. In these mice, subcutaneous WAT was enlarged and associated with increased levels of adiponectin, while hepatic levels of phosphorylated adenosine 5′-monophosphate–activated protein kinase were also increased. In addition, in mice with severe obesity, the expression of hepatic Cd36, Cidea, Cidec, Fabp4, Fasn, and Scd-1 was increased by TZD in a PPARγ-dependent manner. Taken together, these results demonstrate that hepatocyte PPARγ expression offsets the antisteatogenic actions of TZD in mice with severe obesity. Therefore, in obese and insulin resistant humans, TZD-mediated activation of hepatocyte PPARγ may limit the therapeutic potential of TZD to treat NAFLD.

Hepatocyte PPARγ contributes to the progression of non-alcoholic steatohepatitis in male and female obese mice

“…We have previously assessed the effect of hepatocyte PPARγ in the development of steatosis before and after diet-induced obesity is established [14, 16], and before HFCF-induced NASH [13]. In this study, feeding a HFD (60% Kcal from fat) for 34 weeks did not significantly increase liver weight in male or female mice as compared to their LFD-fed littermates ( Figure 5A ).…”

“…Similarly, the expression of PPARγ is also increased in the livers of mouse models with NAFLD [13–23]. Our group has recently reported that the loss of hepatocyte-specific expression of PPARγ (Pparg ΔHep ), before and after the development of diet-induced obesity in adult male mice, reduced diet-induced liver steatosis [14, 16] . Furthermore, we have shown that Pparg ΔHep reduced the progression of steatohepatitis in mice fed a methionine and choline deficient diet [15], and NASH in mice fed a high fat, fructose and cholesterol (HFCF) diet [13].…”

“…Furthermore, we have shown that Pparg ΔHep reduced the progression of steatohepatitis in mice fed a methionine and choline deficient diet [15], and NASH in mice fed a high fat, fructose and cholesterol (HFCF) diet [13]. While these findings are relevant, a methionine and choline deficient diet reduces body weight and insulin resistance, and 24 weeks of the HFCF diet failed to promote obesity or insulin resistance that regular high fat diets (HF, HFD) do [13, 14, 24]. Considering that obesity and T2DM are major risk factors for the development and progression of NAFLD, it is critical to determine if the expression of PPARγ in hepatocytes promotes NASH in mice with pre-established diet- induced obesity.…”

Considerations When Choosing High-Fat, High-Fructose, and High-Cholesterol Diets to Induce Experimental Nonalcoholic Fatty Liver Disease in Laboratory Animal Models

“…At week 24, thermoneutrality accelerated NASH (NAS score: 6 at 29°C compared with 4 at 22°C, hepatocyte ballooning) and fibrosis development (fibrosis stage: 1C at 29°C compared with 1A at 22°C, increased expression of Col1a1 and Collagen Type IV Alpha 1 Chain); however, housing temperature did not further affect adiposity or parameters of insulin resistance. These robust models have also been shown to be an effective tool for identifying the key cell types that are involved in the pathogenesis of NAFLD ( 37 ), therapeutic targets such as hepatic thyroid hormone receptor β ( 38 ), and characterizing therapies for NAFLD with drugs and compounds such as nitro-oleic acid ( 30 ), rosiglitazone ( 39 ), and incretin ( 40 ) among others.…”

Protective effect of rosiglitazone on microscopic and oxidative stress parameters of ram sperm after freeze-thawing

“…Rosiglitazone is categorized in a class of drugs known as 'thiazoledinediones' or 'glitazones', which sensitize the cells in the body to the action of insulin 5 . It is a PPAR-γ (peroxisome proliferator-activated receptor-) agonist that has been shown to have anti brotic and anti-in ammatory effects in some renal diseases 6 .…”