Angiopoietin-like 8 Improves Insulin Resistance and Attenuates Adipose Tissue Inflammation in Diet-Induced Obese Mice.

Angiopoietin-like 8 (ANGPTL8) is closely linked to obesity-associated metabolic diseases and insulin resistance. The aim of the current study was to investigate the ability of ANGPTL8 to reverse insulin resistance in obese mice. The administration of ANGPTL8 reduced weight gain and improved glucose tolerance in mice with diet-induced obesity. In addition, ANGPTL8 administration modified macrophage infiltration, reduced monocyte chemoattractant protein-1 (MCP-1) and interleukin-1ß(IL-1ß) levels, and increased adiponectin gene expression in inguinal white adipose tissue (iWAT). Moreover, the exposure of a cultured peritoneal macrophage line to ANGPTL8 reduced the mRNA expression of M1 macrophage markers (TNF-α and IL-1ß) upon stimulation with lipopolysaccharides in a dose-dependent manner. By contrast, when incubated with IL-4, exposure of macrophages to ANGPTL8 increased the mRNA expression of M2 macrophage markers (Arg1 and Chi3l3) in a dose-dependent manner. Collectively, the results of the present study demonstrated that treatment with ANGPTL8 can attenuate adipose tissue inflammation through regulation of macrophage polarization, and thus, it could be useful for improving insulin resistance.

Bacteria-Derived Recombinant Human ANGPTL8/Betatrophin Significantly Increases the Level of Triglyceride.

ANGPTL8/Betatrophin has been implicated in the regulation of both glucose and triglyceride metabolism. However, its role in regulating glucose metabolism by promoting ß cell proliferation remains controversial, and its physiological functions and molecular targets are largely unknown. Hence, it is of great importance to make recombinant protein and test its effects on ß cell mass directly. In this study, the mature form gene of human ANGPTL8/betatrophin was obtained through chemical synthesis on to the vector pUCE, and the fusion protein was expressed in the Transetta (DE3)/pEASY-E2-betatrophin strain. The inclusion bodies were solubilized in urea and purified by Ni-NTA affinity chromatography. The yield of purified ANGPTL8/betatrophin was approximately 20 mg per liter of culture medium. In vitro studies revealed that the recombinant ANGPTL8/betatrophin had no proliferation effect on MIN6 cells but promoted TG levels in HepG2 cells. This method to generate bioactive ANGPTL8/betatrophin is a simple, practical and user-friendly protocol.

Recombinant betatrophin (Angptl­8/lipasin) ameliorates streptozotocin­induced hyperglycemia and ß­cell destruction in neonatal rats.

Betatrophin [also known as lipasin, angiopoietin­like 8 (ANGPTL8), refeeding induced in fat and liver (RIFL), or hepatocellular carcinoma­associated gene TD26], a 22­kDa protein in the angiopoietin­like family, is a liver­derived hormone that promotes pancreatic ß­cell proliferation and lipid metabolism. The aim of the present study was to investigate the effect of recombinant betatrophin on ß­cell regeneration in a neonatal streptozotocin (STZ)­induced diabetic rat model. One­day­old Wistar rats were injected with STZ (100 mg/kg), followed by intraperitoneal administration of betatrophin to the STZ­injected rats for 6 days. Plasma glucose and body weight were monitored. On days 4 and 7, expression levels of pancreatic duodenal homeobox gene­1 (PDX­1), the Bax/B­cell lymphoma­2 (Bcl­2) ratio and plasma insulin were assessed, and the ß­cell proliferation rate was determined. Pancreatic islet area and number were determined at 10 weeks. It was found that betatrophin treatment alleviated STZ­induced hyperglycemia, elevated pancreatic expression levels of Bcl­2, PDX­1, plasma insulin levels and the ß­cell proliferation rate on days 4 and 7. Long­term betatrophin treatment improved glucose tolerance, associated with improved plasma insulin levels and ß­cell mass. These results suggest that early administration of betatrophin promotes ß­cell proliferation in STZ­induced diabetic neonates and prevents the development of diabetes in adults.

Efecto de la inhibición de la proteína símil angiopoyetina tipo 3 (ANGPTL3): utilidad para el tratamiento de las dislipemias graves / Angiopoietin-like type 3 (angptl) inhibition: its role in the treatment of severe dyslipidemia

Las variantes de ANGPTL3 con pérdida de función están asociadas con efectos beneficiosos sobre el metabolismo lipídico y de carbohidratos y con riesgo reducido de enfermedad coronaria. Los cambios beneficiosos en los parámetros lipídicos que se obtienen con la inhibición de ANGPTL3 junto con la reducción en aterosclerosis que se observa en modelos animales y en estudios epidemiológicos de genética humana hacen de ANGPTL3 un nuevo objetivo terapéutico para prevenir las enfermedades cardiovasculares. Dos estrategias novedosas han surgido para inhibir esta proteína: un anticuerpo monoclonal y un oligonucleótido antisentido, con capacidad para reducir tanto el colesterol como los triglicéridos plasmáticos en forma notoria. Aunque el horizonte es promisorio, todavía no sabemos si los efectos de una variante presente desde el comienzo de la vida serán reproducidos por la inhibición de esta proteína que se realiza más tarde en la vida a través de una intervención farmacológica. (AU)

Loss-of-function ANGPTL3 variants are associated with beneficial effects on carbohydrate and lipid metabolism, and reduced risk of coronary heart disease. The beneficial changes in lipid parameters obtained by ANGPTL3 inhibition together with atheroprotection observed in animal models and in epi-demiological studies of human genetics make ANGPTL3 a new therapeutic target to prevent cardiovascular diseases. Two novel strategies have emerged to inhibit this protein: a monoclonal antibody and an antisense oligonucleotide, with the ability to significantly lower plasma cholesterol and triglycerides. Although the horizon is promising, we still do not know if the effects of a variant present from the beginning of life will be reproduced by the inhibition of this protein that takes place later in life through a pharmacological intervention. (AU)