Abstract
AIMS: Methionine restriction (MR) and hepatic protein tyrosine phosphatase 1B (PTP1B) knockdown both improve hepatic insulin sensitivity by targeting different proteins within the insulin signaling pathway, as well as diminishing hepatic triglyceride content through decreasing hepatic lipogenesis. We hypothesized that a combined approach of hepatic PTP1B inhibition and methionine restriction could lead to a synergistic effect on improvements in glucose homeostasis and lipid metabolism. METHODS: Male and female hepatic PTP1B knockout (Alb-Ptp1b(-/-)) and control wild-type (Ptp1b(fl/fl)) mice were maintained on control diet (0.86% methionine) or MR diet (0.172% methionine) for 8weeks. Body weight and food intake were recorded and physiological tests for whole-body glucose homeostasis were performed. Serum and tissues were analyzed biochemically. RESULTS: MR decreased body weight and increased food intake in Ptp1b(fl/fl) mice as expected, without changing PTP1B protein expression levels or activity. In females, MR treatment alone improved glucose tolerance in Ptp1b(fl/fl) mice, which was further amplified with hepatic PTP1B deficiency. However, other markers of glucose homeostasis were similar between MR-fed groups. In males, MR improved glucose homeostasis in both, Alb-Ptp1b(-/-) and wild-type Ptp1b(fl/fl) mice to a similar extent. Hepatic PTP1B inhibition in combination with MR could not further enhance insulin-stimulated hepatic protein kinase B/Akt phosphorylation compared to MR treatment alone and therefore led to no further increase in hepatic insulin signaling. The combined treatment did not further improve lipid metabolism relative to MR diet alone. CONCLUSIONS: Methionine restriction improves glucose and lipid homeostasis; however, adding hepatic PTP1B inhibition to MR is unlikely to yield any additional protective effects.