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

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.

Hepatocyte Nuclear Factor 4-α (HNF4α) controls the insulin resistance-induced pancreatic ß-cell mass expansion.

BACKGROUND: Regardless of the etiology, any type of DM presents a reduction of insulin-secreting cell mass, so it is important to investigate pathways that induce the increase of this cell mass. AIM: Based on the fact that (1) HNF4α is crucial for ß-cell proliferation, (2) DEX-induced IR promotes ß-cell mass expansion, and (3) the stimulation of ß-cell mass expansion may be an important target for DM therapies, we aimed to investigate whether DEX-induced proliferation of ß pancreatic cells is dependent on HNF4α. METHODS: We used WildType (WT) and Knockout (KO) mice for HNF4-α, treated or not with 100 mg/Kg/day of DEX, for 5 consecutive days. One day after the last injection of DEX the IR was confirmed by ipITT and the mice were euthanized for pancreas removal. RESULTS: In comparison to WT, KO mice presented increased glucose tolerance, lower fasting glucose and increased glucose-stimulates insulin secretion (GSIS). DEX induced IR in both KO and WT mice. In addition, DEX-induced ß-cell mass expansion and an increase in the Ki67 immunostaining were observed only in WT mice, evidencing that IR-induced ß-cell mass expansion is dependent on HNF4α. Also, we observed that DEX-treatment, in an HNF4α-dependent way, promoted an increase in PDX1, PAX4 and NGN3 gene expression. CONCLUSIONS: Our results strongly suggest that DEX-induced IR promotes ß-cell mass expansion through processes of proliferation and neogenesis that depend on the HNF4α activity, pointing to HNF4α as a possible therapeutic target in DM treatment.