Research articleNicotinamide improves glucose metabolism and affects the hepatic NAD-sirtuin pathway in a rodent model of obesity and type 2 diabetes☆
Introduction
Nicotinamide adenine dinucleotide (NAD) is a classic coenzyme that exerts its biological effects via redox and non-redox reactions. NAD is synthesized from tryptophan and two major forms of niacin, nicotinic acid (NA) and nicotinamide (NAM). NAM is used predominantly for NAD biosynthesis in mammals [1], [2], which consists of two enzymatic processes by nicotinamide phosphoribosyltransferase (Nampt) and NAM/NA mononucleotide adenylyltransferase [3], [4]. Nampt is a rate-limiting enzyme for NAD synthesis from NAM and regulates Sirt1-mediated function by modulating NAD availability [5].
Sirtuins are NAD-dependent deacetylases that regulate glucose and lipid metabolism and are implicated in the pathophysiology of aging, diabetes, and hepatic steatosis [6]. Sirt1 overexpression protects against high fat (HF) diet-induced metabolic damages, including glucose intolerance, hepatic steatosis, and inflammation [7], but Sirt1 heterozygous mice develop liver steatosis [8]. Similarly, Sirt6 is involved in glucose homeostasis by modulating hypoxia-inducible factor 1 alpha activity, glucose uptake, and glycolysis [9], [10], and its overexpression in mice has positive effects on serum and liver lipids, visceral fat accumulation, and glucose tolerance [11]. In addition, recent data have demonstrated that other sirtuins, including Sirt2 and 3, have profound roles in metabolic regulation [12], [13], [14], [15].
However, the effect of NA and NAM on fuel metabolism is not settled. The most evident metabolic benefit of NA is its hypolipidemic effect at a high dose of 1–3 g. Glucose metabolism in KK-Ay obese mice improves with NA treatment, accompanied by reduced levels of liver and adipose tissue triglycerides (TG) and serum tumor necrosis factor alpha [16]. In contrast, more recent findings demonstrate NA-induced aggravation of glycemic control via inhibition of glucose-stimulated insulin secretion in murine islet beta cells [17] and alterations in gene expression and basal lipolysis in rat adipose tissue [18]. The regulatory effect of NA on sirtuins has not been reported clearly. NAM has been suggested to be effective for preventing the onset of type 1 diabetes [19], but human clinical trials failed to demonstrate preventive effects [20], [21]. Thus, it is unclear whether NAM has positive or negative effects with regard to insulin resistance or type 2 diabetes. One possible explanation for the scarcity of existing evidence and ambiguous observations regarding the metabolic effects of NAM is that NAM modulates sirtuin system in a complex way. NAM acts as a favorable NAD donor as well as an effective Sirt1 inhibitor; NAM favors NAD biosynthesis under specific stress conditions resulting in NAD depletion (e.g., cerebral ischemia) [22], [23]. In contrast, NAM inhibits Sirt1 activity in vitro and in vivo under various conditions by (1) non-competitively inhibiting conformational changes in sirtuin in response to NAD binding and NAD cleavage in the C pocket of sirtuin and (2) competitively against NAD for binding to the C pocket of sirtuin [24], [25], [26].
Given that NAD is required for maintaining sirtuin activities and exerting their metabolic functions and that comparative metabolic regulation experiments of different NAD donors have not yet been reported, we tested whether the two main NAD donors, NA and NAM, differentially affect glucose metabolism, NAD biology and sirtuin system in a rodent model of obesity and type 2 diabetes. Because the liver is one of the major metabolic organs, we focused on the hepatic NAD-sirtuin system. Additionally, the effects of NA and NAM on proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1 alpha) expression and mitochondrial biogenesis were analyzed.
Section snippets
Animal care
Male OLETF rats were provided by Otsuka Pharmaceutical (Tokushima, Japan). The rats were maintained in a temperature- and humidity-controlled room on a 12 h light/dark cycle and fed standard irradiated rodent chow (5% wt/wt fat; Purina Mills, Richmond, IN, USA) with unlimited access to food and water. Thirty rats, at approximately 28 weeks of age, were divided into five groups: (1) HF diet (45% calories from fat; Research Diets, New Brunswick, NJ, USA; n=8), (2) HF diet and 10 mg NA/kg body
Body weights, food intake, and water intake
Body weights were similar among all groups at baseline. No significant differences were observed in weight change, food intake, or water intake after 4 weeks of treatment (Table 2). No toxicity was observed from any treatment based on monitoring changes in body weight and daily activities during the treatment period.
Nicotinamide improves glucose control and reduces serum TG
Patterns of glucose control during the OGTT were similar among groups at baseline (Fig. 1A). The NA 100, NAM 10, and NAM 100 treatments significantly improved glycemic control, as
Discussion
It was well established that NAD is involved in metabolic regulation via redox and non-redox reactions. Dysregulation of NAD metabolism may be related to the development of several metabolic diseases including insulin resistance and type 2 diabetes [29], [30], [31]. However, a comparative study of different NAD donors at various concentrations on regulation of the NAD-sirtuin pathway and related pathophysiological conditions (e.g. impaired glucose homeostasis) has not been reported. Therefore,
Acknowledgments
The authors thank Dr. Ki-Up Lee (Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea) for helpful comments on the manuscript.
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A2009143 to C-Y. P. and 2012R1A1A1004861 to S.J.Y.). The funder had no role in study design, data collection, and analysis and interpretation, decision
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Disclosure statement: There are no conflicts of interest.