Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet

Abstract

The aim of the present study was to evaluate the effects of monotherapies and combinations of drugs on insulin sensitivity, adipose tissue morphology, and pancreatic and hepatic remodelling in C57BL/6 mice fed on a very HF (high-fat) diet. Male C57BL/6 mice were fed on an HF (60% lipids) diet or SC (standard chow; 10% lipids) diet for 10 weeks, after which time the following drug treatments began: HF-T (HF diet treated with telmisartan; 5.2 mg x kg-1 of body weight x day-1), HF-S (HF diet treated with sitagliptin; 1.08 g x kg-1 of body weight.day-1), HF-M (HF diet treated with metformin; 310.0 mg x kg-1 of body weight x day-1), HF-TM (HF diet treated with telmisartan+metformin), HF-TS (HF diet treated with telmisartan+sitagliptin) and HF-SM (HF diet treated with sitagliptin+metformin). Treated groups also had free access to the HF diet, and treatments lasted for 6 weeks. Morphometry, stereological tools, immunostaining, ELISA, Western blot analysis and electron microscopy were used. The HF diet yielded an overweight phenotype, an increase in oral glucose intolerance, hyperinsulinaemia, hypertrophied islets and adipocytes, stage 2 steatosis (>33%), and reduced liver PPAR-alpha (peroxisome-proliferator-activated receptor-alpha) and GLUT-2 (glucose transporter-2) levels, concomitant with enhanced SREBP-1 (sterol-regulatory-element-binding protein-1) expression (P<0.0001). Conversely, all drug treatments resulted in significant weight loss, a reversal of insulin resistance, islet and adipocyte hypertrophy, and alleviated hepatic steatosis. Only the HF-T and HF-TS groups had body weights similar to the SC group at the end of the experiment, and the latter treatment reversed hepatic steatosis. Increased PPAR-alpha immunostaining in parallel with higher GLUT-2 and reduced SREBP-1 expression may explain the favourable hepatic outcomes. Restoration of adipocyte size was consistent with higher adiponectin levels and lower TNF-alpha (tumour necrosis factor-alpha) levels (P<0.0001) in the drug-treated groups. In conclusion, all of the drug treatments were effective in controlling the metabolic syndrome. The best results were achieved using telmisartan and sitagliptin as monotherapies or as a dual treatment, combining partial PPAR-gamma agonism and PPAR-alpha activation in the liver with extended incretin action.

Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

“…Experimental dietary models of NAFLD are influenced by the dietary scheme duration, diet composition, and animal age, all of which directly affect the spectrum of NAFLD pathogenesis [20] . When there is excessive dietary intake of lipids, hepatic PPARalpha expression decreases significantly parallel to an expressive increase of PPAR-gamma [16,21] . Obese mice fed during 16 wk a high-fat (HF) diet made up of 60% of energy as lipids, predominantly saturated fatty acids from lard, exhibited overweight, insulin resistance and 34.57% of volume density of hepatic steatosis concomitant to a proinflammatory adipokine profile and activation of hepatic stellate cells (HSCs) [21] .…”

“…When there is excessive dietary intake of lipids, hepatic PPARalpha expression decreases significantly parallel to an expressive increase of PPAR-gamma [16,21] . Obese mice fed during 16 wk a high-fat (HF) diet made up of 60% of energy as lipids, predominantly saturated fatty acids from lard, exhibited overweight, insulin resistance and 34.57% of volume density of hepatic steatosis concomitant to a proinflammatory adipokine profile and activation of hepatic stellate cells (HSCs) [21] . Hepatic PPAR-alpha expression was substantially reduced [21] , agreeing with a reduced number in the numerical density of hepatic mitochondria [21,22] .…”

“…The significant weight gain after pioglitazone treatment was an adverse effect [65] . Recently, the partial activation of PPAR-gamma coupled with the selective activation of PPAR-alpha in the liver by telmisartan (also an AT1 receptor blocker) elicited positive effects to hepatic cytoarchitecture and ultrastructure in mice fed a HF diet [21,66] . Animals showed normal volume density of hepatic steatosis when compared to the untreated group, followed by reduced SREBP-1c expression and insulinemia parallel to greater mitochondrial numerical density revealed by transmission electron microscopy [21] .…”

“…Obese mice fed during 16 wk a high-fat (HF) diet made up of 60% of energy as lipids, predominantly saturated fatty acids from lard, exhibited overweight, insulin resistance and 34.57% of volume density of hepatic steatosis concomitant to a proinflammatory adipokine profile and activation of hepatic stellate cells (HSCs) [21] . Hepatic PPAR-alpha expression was substantially reduced [21] , agreeing with a reduced number in the numerical density of hepatic mitochondria [21,22] . PPAR-alpha is related to mitochondrial beta-oxidation of fatty acids, which has got carnitine palmitoyl transferase-1 (CPT-1) as a pivotal enzyme that allows the fatty acid to go through the inner mitochondrial membrane and reach the mitochondrial matrix to be metabolized [23] .…”

Metformin and Pancreatic Cancer Metabolism

“…The mRNA and nuclear protein levels of SREBP-2 were also reduced after metformin treatment. This AMPK-mediated suppression of SREBP-1c has also been reported to prevent lipogenesis in an insulin resistant mouse model [20] and is consistent with a decrease in hepatic SREBP-1 expression in mice fed a high fat (60% lipids) diet for 10 weeks and then metformin (0.48mg% of the diet) for another six weeks [100]. Since SREBP-1c and SREBP-2 are transcription factors that promote the expression of enzymatic genes involved in fatty acid and cholesterol synthesis, respectively [101] we would expect diminished lipid synthesis as a biological endpoint of their downregulation.…”