Immunotherapy against angiotensin II receptor ameliorated insulin resistance in a leptin receptor‐dependent manner

Abstract

The angiotensin II type 1 receptor (AT1R) signaling pathway is reported to modulate glucose metabolism. Targeting AT1R, our group invented ATRQβ-001 vaccine, a novel immunotherapeutic strategy to block the activation of AT1R. Here, we evaluated the therapeutic efficacy of ATRQβ-001 vaccine in insulin resistance, and investigated the mechanism. Our results showed that ATRQβ-001 vaccine and specific monoclonal antibody against epitope ATR-001 (McAb-ATR) decreased fasting serum insulin concentration and improved glucose and insulin tolerance in ob/ob mice. These beneficial effects were verified in high-fat diet-induced obese mice. McAb-ATR activated insulin signaling in skeletal muscle and insulin-resistant C2C12 myotubes without affecting liver or white adipose tissue of ob/ob mice. Mechanistically, the favorable impact of McAb-ATR on insulin resistance was abolished in db/db mice and in C2C12 myotubes with leptin receptor knockdown. AT1R knockdown also eradicated the effects of McAb-ATR in C2C12 myotubes. Furthermore, McAb-ATR treatment was able to activate the leptin receptor-mediated JAK2/STAT3 signaling in skeletal muscle of ob/ob mice and C2C12 myotubes. Additionally, angiotensin II downregulated the leptin signaling in skeletal muscle of ob/ob and diet-induced obese mice. We demonstrated that ATRQβ-001 vaccine and McAb-ATR improved whole-body insulin resistance and regulated glucose metabolism in skeletal muscle in a leptin receptor-dependent manner. Our data suggest that immunotherapy targeting AT1R is a novel strategy for treating insulin resistance.

miR-186-5p Dysregulation in Serum Exosomes from Patients with AMI Aggravates Atherosclerosis via Targeting LOX-1

“…Western blot was done following previously described protocols. 23 Total proteins of exosomes, cells, and arterial tissues were extracted using the RIPA lysis buffer (Beyotime, Shanghai, China). After electroblotting, the membranes were blocked with 3% BSA (Sigma-Aldrich, USA) and then incubated with primary antibodies against CD63 (1:1000, Abcam, Cambridgeshire, UK), CD81 (1:1000, Abcam), tumor susceptibility gene 101 (Tsg101, 1:500, Proteintech, Rosemont, USA), LOX-1 (1:1000, Abcam), and β-actin (1:1000, Proteintech) overnight at 4°C.…”

Obesity modulates cell-cell interactions during ovarian folliculogenesis

“…We first used two widely corroborated genetic models, leptin knockout (Lep KO) and leptinreceptor knockout (Lepr KO) mice (Figure S1A). Due to leptin deficiency in Lep KO mice or leptin receptor loss-of-function in Lepr KO mice, these two mouse lines developed severe hyperphagia and spontaneous obesity, accompanying the resulting metabolic disorders including insulin-resistance and impaired glucose homeostasis (Chen et al, 2021;Jia et al, 2020;Pan et al, 2021;Tao et al, 2020;Zheng et al, 2021aZheng et al, , 2021b. We also used high-fat diet feeding to obtain HFD mice (Figure S1B).…”

Pioglitazone Synthetic Analogue Ameliorates Streptozotocin-Induced Diabetes Mellitus through Modulation of ACE 2/Angiotensin 1–7 via PI3K/AKT/mTOR Signaling Pathway

“…In contrast to the traditional RAS system, stimulation of the Ang II-Ang (1–7) axis has been shown to have powerful antioxidant and anti-inflammatory effects [ 12 ]. On the other hand, the RAS and leptin signaling pathway has been investigated to have linked cross talk through regulating glucose metabolism [ 13 ].…”

“…Furthermore, both IRS 1 and IRS 2 are widely expressed in hepatocytes; IRS 1 may be more responsible for glucose management, while IRS 2 may govern lipid handling [ 14 ]. In the presence of insulin, the downstream phosphoinositide 3-kinase (PI3K) signaling cascade is activated, leading to the activation of Akt and other downstream transmitters, such as IB kinase, ERK, JNK, PiK3, and mTOR, which negatively phosphorylate IRS proteins on their specific sites and inhibit their activity [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. The activation of the PI3K/AKT/mTOR intracellular signaling pathway resulted in the translocation of insulin-regulated glucose transporter-4 (GLUT 4) into the plasma protein, facilitating glucose absorption through insulin response sites.…”