Efeitos do LDT409 sobre o metabolismo energético e remodelamento hepático em camundongos alimentados com dieta rica em frutose

Abstract

Excessive fructose intake, present in ultra-processed foods, is correlated with non-alcoholic fatty liver disease (DGHNA) and insulin resistance (IR). IR compromises endoplasmic reticulum homeostasis, producing a pro-inflammatory effect due to the imbalance of metabolic pathways regulated by transcription factors, such as receptors activated by peroxisomal proliferation (PPARS). This study sought to evaluate the effects of LDT409 (PPAR-alpha / gamma duplex agonist) on hepatic structural remodeling, highlighting energy metabolism and hepatic endoplasmic reticulum stress in mice fed a high-fructose diet. Forty-six male C57BL / 6 mice (three months old) were randomly assigned to receive either a control diet or a high-fructose diet for ten weeks. Then, groups were subdivided into four groups to start the treatment for five weeks: C, CT (diet C + LDT409), HFRU, HFRU (diet HFRU + LDT409). The treatment was added to the diets at a dose of 40 mg/kg of body weight. HFRU animals showed increased intra-abdominal fat, IR, reduced beta-oxidation and increased gluconeogenesis, lipogenesis, and fibrogenesis. The evaluated data suggest activation of hepatic stellate cells after 17 weeks of HFRU diet. On the other hand, the treatment normalized these parameters, exerting anti-steatotic effects and preventing the activation of the stellate cells in this model by reducing lipogenesis and controlling the endoplasmic reticulum stress concomitant with the increase in beta-oxidation of fatty acids in hepatocyte mitochondria. LDT409 may represent a potential nutraceutical for NAFLD, which does not currently have a drug directed to its control.Excessive dietary intake of saturated fat causes an imbalance in energy homeostasis, which is one of the leading causes for the development of obesity and, consequently, adipocyte dysfunction. Peroxisome proliferator-activated receptor-α (PPAR-α) plays a paramount role in the browning of white adipocytes, as well as dipeptidyl peptidase-4 inhibitors (DPP-4i) can enhance thermogenesis. This study sought to evaluate the association of the PPAR-alpha agonist (WY14643) and DPP-4i (linagliptin) on the subcutaneous white adipose tissue remodeling and thermogenesis induction in mice fed a high-fat diet. Forty male C57BL/6 mice (three months old) were randomly assigned to receive a control diet (C, 10% energy as lipids) or a high-fat diet (HF, 50% energy as lipids) for twelve weeks. Then, each group was subdivided into two groups to start the treatment that lasted five weeks: C, CT (C diet plus PPAR-α agonist and DPP-4i), HF, and HFT (HF diet plus PPAR-α agonist and DPP-4i). Drugs were mixed to the diets at a dose of 2.5 mg/kg body mass for WY14643 and 15 mg/kg body mass for linagliptin. The animals in the HF group showed overweight, oral glucose intolerance, adipocyte hypertrophy, substantial accumulation of intra-abdominal and subcutaneous fat. Conversely, the treatment was able to normalize these parameters, besides increasing the body temperature, the presence of multilocular adipocytes (beige), and the high expression of thermogenic markers genes. These observations point to the activation of the browning cascade in the subcutaneous white adipose tissue concomitant with noticeable anti-inflammatory effects and endoplasmic reticulum stress alleviation. Hence, the association of the PPAR-α agonist with DPP-4i emerges as a promising target for obesity control through the induction of beige cells and adaptive thermogenesis.