Research article
Nicotinamide improves glucose metabolism and affects the hepatic NAD-sirtuin pathway in a rodent model of obesity and type 2 diabetes

https://doi.org/10.1016/j.jnutbio.2013.09.004Get rights and content

Abstract

Nicotinic acid (NA) and nicotinamide (NAM) are major forms of niacin and exert their physiological functions as precursors of nicotinamide adenine dinucleotide (NAD). Sirtuins, which are NAD-dependent deacetylases, regulate glucose and lipid metabolism and are implicated in the pathophysiology of aging, diabetes, and hepatic steatosis. The aim of this study was to investigate the effects of two NAD donors, NA and NAM, on glucose metabolism and the hepatic NAD-sirtuin pathway. The effects were investigated in OLETF rats, a rodent model of obesity and type 2 diabetes. OLETF rats were divided into five groups: (1) high fat (HF) diet, (2) HF diet and 10 mg NA/kg body weight (BW)/day (NA 10), (3) HF diet and 100 mg NA/kg BW/day (NA 100), (4) HF diet and 10 mg NAM/kg BW/day (NAM 10), and (5) HF diet and 100 mg NAM/kg BW/day (NAM 100). NA and NAM were delivered via drinking water for four weeks. NAM 100 treatment affected glucose control significantly, as shown by lower levels of accumulative area under the curve during oral glucose tolerance test, serum fasting glucose, serum fasting insulin, and homeostasis model assessment of insulin resistance, and higher levels of serum adiponectin. With regard to NAD-sirtuin pathway, intracellular nicotinamide phosphoribosyltransferase, NAD, the NAD/NADH ratio, Sirt1, 2, 3, and 6 mRNA expressions, and Sirt1 activity all increased in livers of NAM 100-treated rats. These alterations were accompanied by the increased levels of proliferator-activated receptor gamma, coactivator 1 alpha and mitochondrial DNA. The effect of NA treatment was less evident than that of NAM 100. These results demonstrate that NAM is more effective than NA on the regulation of glucose metabolism and the NAD-sirtuin pathway, which may relate to the altered mitochondrial biogenesis.

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

References (42)

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