The ability of Sirtuin gain-of-function to extend lifespan and improve metabolism in simple organisms, together with the insulin-sensitizing properties of Sirtuin agonists in rodents, have led to the exploration of this pathway for therapeutic ends in metabolic disease. But a rigorous genetic test of the hypothesis that Sirtuin gain-of-function results in positive metabolic effects has not been carried out.
Two models of SirT1 gain-of-function had previously been reported. SirT1 overexpression in β cells increased insulin secretion (Moynihan et al., 2005
). SirBACO mice did not show this phenotype, possibly due to differences in the levels of SirT1 expression. In SirT1 knock-in mice (Bordone et al., 2007
), the transgene is expressed off the β-actin locus, leading potentially to developmental effects that impair adipocyte differentiation (Picard et al., 2004
), and increase insulin sensitivity. Thus, the SirT1 knock-in model cannot distinguish between a direct effect of SirT1 and an indirect one due to reduced body fat.
Complex metabolic effects of SirT1 overexpression
Our results demonstrate complex, and not easily generalizable effects of SirT1 over-expression. In chow-fed mice, SirT1 gain-of-function has no discernible effects on insulin sensitivity and glucose utilization, but engenders a behavioral response that partly mimics calorie restriction. While further studies will be required to dissect the site(s) of these Sirtuin effects, they are likely to reflect an involvement of the central nervous system, and thus point to the need for rigorous behavioral/psychometric testing in early-phase clinical trials of Sirtuin agonists. In light of the current prevalence of overweight, the effects of SirT1 to reduce food intake are of some interest. In the present study we cannot identify whether these effects are mediated directly in the central nervous system, or by circulating factors.
Resveratrol-treated mice fed a HFD display increased O2
consumption (Lagouge et al., 2006
) and decreased body weight, (Baur et al., 2006
; Lagouge et al., 2006
). SirBACO mice on a HFD do not display these phenotypes, but–similar to resveratrol-treated mice–show decreased locomotor activity (Lagouge et al., 2006
). The data suggest that resveratrol acts on additional Sirtuins or on different targets. While both exogenous resveratrol and SirT1 overexpression improve glucose tolerance in high fat–fed and db/db
mice, the mechanisms appears to differ: our studies point to a mechanistic link with hyperadiponectinemia, while improved ATP utilization seems to protect resveratrol-treated mice from diet-induced diabetes (Baur et al., 2006
; Lagouge et al., 2006
). The hyperadiponectinemia model allows us to reconcile the decreased hepatic glucose production in SirBACO mice with SirT1’s ability to increase it (Rodgers et al., 2005
). We propose that, in SirBACO mice, the insulin-sensitizing effect of adiponectin trumps SirT1’s cell-nonautonomous activation of the gluconeogenic program.
In vivo SirT1 substrates and metabolic control
, the FoxO1 ortholog daf-16
is required for lifespan extension in response to SirT1 gain-of-function (Tissenbaum and Guarente, 2001
). The widespread role of FoxO1 in mammalian metabolism provides a testable hypothesis on SirT1’s mechanism of action. In this regard we found that, unlike common forms of obesity and type 2 diabetes (Hu et al., 1996
), SirBACO mice in diabetic and obese backgrounds display increased adiponectin. We propose that SirT1 acts through FoxO1 to increase adiponectin production. Given the conflicting results on the effect of SirT1 on adiponectin expression (Qiang et al., 2007
; Qiao and Shao, 2006
), the hyperadiponectinemia of SirBACO mice may have heterogeneous causes, including changes in β-adrenergic signaling or redox potential (Fasshauer et al., 2001
; Furukawa et al., 2004
). Nonetheless, this phenotype bears similarities with the effect of adiponectin overexpression in ob/ob
mice (Kim et al., 2007
). Moreover, knock-in mice bearing constitutively deacetylated FoxO1 alleles mimic the energy balance phenotype of SirBACO mice, supporting the contention that the effects of SirT1 are mediated by FoxO1 (A.B. and D.A., unpublished observation).