Central administration of resveratrol improves diet-induced diabetes

Abstract

Resveratrol is a natural polyphenolic compound that activates nicotinamide adenosine dinucleotide-dependent deacetylase SIRT1. Resveratrol has recently been shown to exert potent antidiabetic actions when orally delivered to animal models of type 2 diabetes. However, the tissue(s) mediating these beneficial effects is unknown. Because SIRT1 is expressed in central nervous system (CNS) neurons known to control glucose and insulin homeostasis, we hypothesized that resveratrol antidiabetic effects are mediated by the brain. Here, we report that long-term intracerebroventricular infusion of resveratrol normalizes hyperglycemia and greatly improves hyperinsulinemia in diet-induced obese and diabetic mice. It is noteworthy that these effects are independent of changes in body weight, food intake, and circulating leptin levels. In addition, CNS resveratrol delivery improves hypothalamic nuclear factor-kappaB inflammatory signaling by reducing acetylated-RelA/p65 and total RelA/p65 protein contents, and inhibitor of nuclear factor-kappaB alpha and IkappaB kinase beta mRNA levels. Furthermore, this treatment leads to reduced hepatic phosphoenolpyruvate carboxykinase 1 mRNA and protein levels and ameliorates pyruvate-induced hyperglycemia in this mouse model of type 2 diabetes. Collectively, our results unveiled a previously unrecognized key role for the CNS in mediating the antidiabetic actions of resveratrol.

Figures

Figure 1

CNS resveratrol administration activates SIRT1 only in the brain. Acetylated lysine (K) 379 in p53 and β-actin (used as loading control) protein levels were assessed in the forebrain (without the hypothalamus) (A) and liver (B) of HC-saline and HC-resveratrol mice by Western blot analysis. Error bars, sem. Statistical analyses were done using two-tailed unpaired Student’s t test. *, P < 0.05.

Figure 2

CNS resveratrol administration does not improve energy balance. A, Body weight before and 5 wk after surgery in HC-saline and HC-resveratrol C57BL/6 male mice. B, Daily food intake in the postsurgery period in HC-saline and HC-resveratrol mice. The chow-fed group consists of age-matched, C57BL/6 male mice fed ad libitum on a regular chow diet that did not undergo any surgical procedure. Error bars, sem. Statistical analyses were done using two-tailed unpaired Student’s t test or one-way ANOVA (Tukey’s post test) when two or three groups were compared, respectively (n = 7 for each group). ***, P < 0.001 vs. HC-saline mice.

Figure 3

CNS resveratrol administration improves glucose homeostasis. Blood glucose (A) and serum insulin levels (B) before and 5 wk after surgery in fed HC-saline and HC-resveratrol C57BL/6 male mice. The chow-fed group consists of age-matched, C57BL/6 male mice fed ad libitum on a regular chow diet that did not undergo any surgical procedure. Error bars, sem. Statistical analyses were done using one-way ANOVA (Tukey’s post test). (n = 7 for each group.) **, P < 0.01; ***, P < 0.001 vs. HC-saline mice. NS, Not statistically different.

Figure 4

CNS resveratrol administration improves brain NF-kB signaling. A, RelA/p65, Ac-RelA/p65(K310) and β-actin (used as loading control) protein levels (determined by Western blot analysis) were assessed in hypothalamus of HC-saline, HC-resveratrol, and chow-fed, age-matched, C57BL/6 male mice (n = 7 for each group). Iκ-Bα (B) and IKKβ (C) mRNA level in hypothalamus, hindbrain, and liver (determined by quantitative real-time PCR). Error bars, sem. Statistical analyses were done using one-way ANOVA (Tukey’s post test). *, P < 0.05; **, P < 0.01; ***, P < 0.001 vs. HC-saline mice.

Figure 5

CNS resveratrol administration improves hepatic PEPCK expression and Pyruvate-induced hyperglycemia. Pepck and G6Pase mRNA level (determined by quantitative real-time PCR) (A) and PEPCK and β-actin (used as loading control) protein levels (determined by Western blot analysis) (B) were assessed in liver of HC-saline, HC-resveratrol, and chow-fed, age-matched, C57BL/6 male mice (n = 6–7 for each group). C, Blood glucose levels over time after a pyruvate tolerance test in a different cohort 5 wk after treatment (n = 7 for each group). Error bars, sem. Statistical analyses were done using one-way ANOVA (Tukey’s post test). *, P < 0.05; **, P < 0.01; ***, P < 0.001 vs. HC-saline mice. D, A proposed model of action through which brain-specific SIRT1 activators may suppress diet-induced brain inflammation leading to improved hyperglycemia and hyperinsulinemia.