Pep19 Has a Positive Effect on Insulin Sensitivity and Ameliorates Both Hepatic and Adipose Tissue Phenotype of Diet-Induced Obese Mice

Abstract

Peptide DIIADDEPLT (Pep19) has been previously suggested to improve metabolic parameters, without adverse central nervous system effects, in a murine model of diet-induced obesity. Here, we aimed to further evaluate whether Pep19 oral administration has anti-obesogenic effects, in a well-established high-fat diet-induced obesity model. Male Swiss mice, fed either a standard diet (SD) or high-fat diet (HFD), were orally administrated for 30 consecutive days, once a day, with saline vehicle or Pep19 (1 mg/kg). Next, several metabolic, morphological, and behavioral parameters were evaluated. Oral administration of Pep19 attenuated HFD body-weight gain, reduced in approximately 40% the absolute mass of the endocrine pancreas, and improved the relationship between circulating insulin and peripheral insulin sensitivity. Pep19 treatment of HFD-fed mice attenuated liver inflammation, hepatic fat distribution and accumulation, and lowered plasma alanine aminotransferase activity. The inguinal fat depot from the SD group treated with Pep19 showed multilocular brown-fat-like cells and increased mRNA expression of uncoupling protein 1 (UCP1), suggesting browning on inguinal white adipose cells. Morphological analysis of brown adipose tissue (BAT) from HFD mice showed the presence of larger white-like unilocular cells, compared to BAT from SD, Pep19-treated SD or HFD mice. Pep19 treatment produced no alterations in mice behavior. Oral administration of Pep19 ameliorates some metabolic traits altered by diet-induced obesity in a Swiss mice model.

Neurolysin Knockout Mice in a Diet-Induced Obesity Model

“…Therefore, leptin in parallel to the effects of other cytokines alters centrally regulated thresholds of thermoregulatory mechanisms [91]. Future experiments investigating Nln -/and WT animals, fed either SD or HD, should shed light on the possible contribution of Nln and InPeps to thermoregulation [66,[92][93][94][95][96].…”

“…Therefore, it was suggested that Ric4 contributes to the enhanced glucose uptake and insulin sensitivity observed in Nln -/- [119]. Pep19, identified by means of conformationalsensitive antibodies targeting G-protein coupled receptors [120,121], induced uncoupling protein 1 expression in both white adipose tissue and 3T3-L1 differentiated adipocytes [96] Oral administration of Pep19 into diet-induced obese Wistar rats or Swiss mice significantly reduces whole body weight and the size of adipocytes [95,96]. THOP1 was also shown to play a key role in the metabolism of peptides regulating energy expenditure [28].…”