Novel Gut Microbiota Modulator, Which Markedly Increases Akkermansia muciniphila Occupancy, Ameliorates Experimental Colitis in Rats.

Background: Since gut microbiota is involved in the pathogenesis of inflammatory bowel disease (IBD), antibiotics or probiotics may be attractive options for the treatment of IBD. Akkermansia muciniphila is expected as a next-generation probiotic for IBD, and OPS-2071 is a novel quinolone with potent antibacterial activity against Clostridioides difficile.

Aims: The aim of this study is to assess the potential of OPS-2071 as a gut microbiota modulator for IBD.

Antidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler.

Inducing mitochondrial uncoupling (mUncoupling) is an attractive therapeutic strategy for treating metabolic diseases because it leads to calorie-wasting by reducing the efficiency of oxidative phosphorylation (OXPHOS) in mitochondria. Here we report a safe mUncoupler, OPC-163493, which has unique pharmacokinetic characteristics. OPC-163493 shows a good bioavailability upon oral administration and primarily distributed to specific organs: the liver and kidneys, avoiding systemic toxicities.

Expression of DGAT2 in white adipose tissue is regulated by central leptin action.

Acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes catalyze the final step in mammalian triglyceride synthesis, and their functions are considered to be involved in the mechanisms of obesity, insulin resistance, and leptin resistance. Insulin receptor substrate-2 (IRS-2)-deficient mice exhibit obesity-associated with hypertrophic adipocytes and leptin resistance. Screening for transcripts of genes involved in fatty acid and triglyceride synthesis to investigate the mechanism of the hypertrophic change in the adipocytes showed that expression of DGAT2 mRNA was up-regulated in the white adipose tissue (WAT) of Irs2-/- mice, whereas that of DGAT1 was down-regulated.

Both insulin signaling defects in the liver and obesity contribute to insulin resistance and cause diabetes in Irs2(-/-) mice.

We previously reported that insulin receptor substrate-2 (IRS-2)-deficient mice develop diabetes as a result of insulin resistance in the liver and failure of beta-cell hyperplasia. In this study we introduced the IRS-2 gene specifically into the liver of Irs2(-/-) mice with adenovirus vectors. Glucose tolerance tests revealed that the IRS-2 restoration in the liver ameliorated the hyperglycemia, but the improvement in hyperinsulinemia was only partial.