Lipidized PrRP Analog Exhibits Strong Anti-Obesity and Antidiabetic Properties in Old WKY Rats with Obesity and Glucose Intolerance

Abstract

Prolactin-releasing peptide (PrRP) is an anorexigenic neuropeptide that has potential for the treatment of obesity and its complications. Recently, we designed a palmitoylated PrRP31 analog (palm11-PrRP31) that is more stable than the natural peptide and able to act centrally after peripheral administration. This analog acted as an anti-obesity and glucose-lowering agent, attenuating lipogenesis in rats and mice with high-fat (HF) diet-induced obesity. In Wistar Kyoto (WKY) rats fed a HF diet for 52 weeks, we explored glucose intolerance, but also prediabetes, liver steatosis and insulin resistance-related changes, as well as neuroinflammation in the brain. A potential beneficial effect of 6 weeks of treatment with palm11-PrRP31 and liraglutide as comparator was investigated. Liver lipid profiles, as well as urinary and plasma metabolomic profiles, were measured by lipidomics and metabolomics, respectively. Old obese WKY rats showed robust glucose intolerance that was attenuated by palm11-PrRP31, but not by liraglutide treatment. On the contrary, liraglutide had a beneficial effect on insulin resistance parameters. Despite obesity and prediabetes, WKY rats did not develop steatosis owing to HF diet feeding, even though liver lipogenesis was enhanced. Plasma triglycerides and cholesterol were not increased by HFD feeding, which points to unincreased lipid transport from the liver. The liver lipid profile was significantly altered by a HF diet that remained unaffected by palm11-PrRP31 or liraglutide treatment. The HF-diet-fed WKY rats revealed astrogliosis in the brain cortex and hippocampus, which was attenuated by treatment. In conclusion, this study suggested multiple beneficial anti-obesity-related effects of palm11-PrRP31 and liraglutide in both the periphery and brain.

Metabolomic Study of Aging in fa/fa Rats: Multiplatform Urine and Serum Analysis

“…Surprisingly, significantly lower concentrations of the branched-chain amino acids (BCAAs) valine and leucine were found in the serum of the fa/fa group compared with the lean controls, which was confirmed independently by both NMR and LC-MS analysis. An analogous decrease in plasma valine and leucine was also observed in our recent WKY rat model when the animals were fed a high fat (HF) diet [47]. Park et al detected a decrease in circulating BCAAs in C57BL/6N mice fed an HF diet [50].…”

“…Our study is the first to describe a significant reduction in putrescine, a metabolite of polyamine metabolism, in fa/fa rats. The reduced excretion of putrescine, which might be related to the accumulation of white adipose tissue and obesity development, was also reported in mice with MSG-induced obesity [46] and in WKY with diet-induced obesity [47].…”

LC-MS Lipidomic Analysis of Macrophages

“…I. Analýza probíhala na hmotnostním spektrometru Orbitrap IQ-X Tribrid (Thermo Scientific, USA) spojeném s chromatografickým systémem tvořeným autosamplerem TriPlus RSH Smart 850, kvartérním čerpadlem a kompartmentem na kolony z řady Vanquish (vše Thermo Scientific, USA). Optimalizace vycházela z již publikované LC-MS metody 2 . Mobilní fáze se skládala ze dvou složek.…”