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.2016 Aug 16;16(7):1851-60.
doi: 10.1016/j.celrep.2016.07.027. Epub 2016 Aug 4.

NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice

Affiliations

NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice

Kelly L Stromsdorfer et al. Cell Rep..

Abstract

Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD(+) biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle and adipose tissue dysfunction, manifested by increased plasma free fatty acid concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARγ (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARγ targets in adipose tissue. These deleterious alterations were normalized by administering rosiglitazone or a key NAD(+) intermediate, nicotinamide mononucleotide (NMN). Collectively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ insulin resistance.

Keywords: NAD(+); NAMPT; PPARγ; adipocyte; insulin resistance; obesity.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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Conflict of interest statement

STATEMENT S.I. is a co-founder of Metro Midwest Biotech. Dr. Samuel Klein, Division Chief of Nutritional Science at Washington University in St. Louis (WUSTL), has ownership interests with Metro Midwest Biotech. WUSTL may receive royalty income based on a technology licensed by WUSTL to Metro Midwest Biotech. This technology is evaluated in this research.

Figures

Figure 1
Figure 1. Adipocyte-specificNampt deletion causes multi-organ insulin resistance
Glucose metabolism in female control (flox/flox) and adipocyte-specificNampt knockout (ANKO) mice fed a standard chow. Blood glucose (A) and plasma insulin (B) concentrations during the intraperitoneal glucose tolerance tests (IPGTTs) in 3- to 5- month-old mice (n=6–8 per group). The area under the curve (AUC) for glucose is shown next to the glucose tolerance curves. (C) Blood glucose concentrations during the insulin tolerance tests (ITTs) in 2- to 4- month-old mice (n=7–9 per group). (D-I) Hyperinsulinemic euglycemic clamp procedure (HECP) was performed in 3- to 8- month-old mice (n=9–10 per group). (D) Glucose infusion rate (GIR) during the HECP. Average of GIR during the clamp period is shown next to the GIR curves. (E) Basal and insulin-stimulated rates of hepatic glucose production (HGP). (F) Insulin-stimulated percent suppression of basal HGP. (G) Hepatic gene expression of gluconeogenic enzymes, glucose 6-phospahtase (G6pc) and pyruvate dehydrogenase lipoamide kinase isozyme 4 (Pdk4), after the HECP (n=6–7 per group). (H) Whole-body glucose disposal rates. (I) Insulin-stimulated glucose uptake in skeletal muscle and heart. Values are means ± SE.P-values were determined by Student’s t-test. *,P < 0.05; **,P < 0.01; ***,P < 0.001.
Figure 2
Figure 2. Loss ofNampt induces adipose tissue dysfunction
Adipose tissue function in female control and ANKO mice. (A) Insulin-stimulated glucose uptake in visceral adipose tissue (VAT) during the HECP (n=9–10 per group). Plasma free fatty acids (FFA) concentrations in basal and insulin-stimulated conditions (B) and insulin-stimulated percent suppression during the HECP (C) (n=6–7 per group). (D) Western blot and quantification of phosphorylated AKT (serine-473) and total-AKT in VAT obtained after the HECP (n=5–7 per group). (E) Plasma FFA and triglyceride (TG) concentrations at a fed condition in 4- to 5- month-old mice (n=7–9 per group). (F) Hepatic TG concentrations in 2- to 9- month-old mice (n=15–16 per group). (G) VAT gene expression of inflammatory markers in 4- month-old mice (n=4 per group).Il6; interleukin 6,Tnf; tumor necrosis factor,Mcp-1; monocyte chemoattractant protein 1,Cd68; CD68 antigen. (H) Plasma concentrations of adiponectin and adipsin in 2- to 3- month-old mice (n=6–11 per group). Values are means ± SE.P-values were determined by Student’s t-test. *,P < 0.05; **,P < 0.01; ***,P < 0.001.
Figure 3
Figure 3. ANKO mice have increased phosphorylation of CDK5 and PPARγ (Ser273) and decreased gene expression of obesity-liked phosphorylated PPARγ targets in adipose tissue
Protein levels of phosphorylated PPARγ (Ser273) (A) and CDK5 (B) in VAT obtained from 2- to 3- month-old female control and ANKO mice after overnight fasting. Phosphorylated protein levels were normalized by total protein content. (C) Immunoprecipitated acetylated PPARγ and PPARγ (inputs) were evaluated in VAT. Acetylated PPARγ levels were normalized by PPARγ protein content (n=4 per group). (D) VAT gene expression of obesity-liked phosphorylated PPARγ (S273) targets in female control and ANKO mice (n=4 per group).Cidec; cell death-inducing DFFA-like effector c,Car3; carbonic anhydrase 3,Cyp2f2; cytochrome P450, family 2, subfamily f, polypeptide 2,Selebbp1; Selenium Binding Protein 1,Txnip; thioredoxin interacting protein,Nr3c1; nuclear receptor subfamily 3, group C, member 1,Nr1d1; nuclear receptor subfamily 1, group D, member 1,Nr1d2; nuclear receptor subfamily 1, group D, member 2,Acly; ATP citrate Lyase,Aplp2; amyloid beta (A4) precursor-like protein 2. (E) Female ANKO mice received a chow containing rosiglitazone (RSG; 20 mg/kg-body weight/day). ITTs were performed after 6 weeks of RSG treatment. ITTs results from RSG-treated and age-matched untreated ANKO mice were shown (n=7–12 per group). The AUC for glucose is shown next to the insulin tolerance curves. (F) Plasma insulin concentrations in RSG-treated and -untreated ANKO mice (n=7–10 per group). (G) VAT and subcutaneous adipose tissue (SAT) gene expression of obesity-liked PPARγ (Ser273) targets in RSG-treated and -untreated ANKO mice (n=4–7 per group). (H) Plasma concentrations of adiponectin and adipsin in RSG-treated and -untreated female ANKO mice (n=7–12 per group). (I) Total number of ambulations and instances of vertical rearing in RSG-treated and -untreated male ANKO mice on the 1 h locomotor test (n=5 per group). (J) OP9 adipocytes were cultured with 0.1% DMSO (control), 500 nM FK866, or FK866 plus 30 nM MRL24 (CDK5 inhibitor) for 48 hours and examined for adiponectin and adipsin gene expression (n=3 per group). Values are means ± SE.P-values were determined by Student’s t-test. a,P < 0.05 (control vs. FK866); b,P < 0.05 (FK866 vs. FK866+MRL24) (ANOVA). *,P < 0.05; **,P < 0.01; ***,P < 0.001.
Figure 4
Figure 4. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, normalizes metabolic deragments in ANKO mice
(A) Mammalian NAD+ biosynthetic pathways. Nicotinamide mononucleotide (NMN) is a product of NAMPT-mediated enzymatic reaction and it is directly converted into NAD+. Nicotinic acid (NA) is a precursor for the NAPRT-dependent NAD+ biosynthetic pathway. NIC; nicotinmaide, Trp; tryptophan, NR; nicotinamide riboside, NaMN; nicotinic acid mononucleotide, NAPRT; nicotinic acid phosphoribosyltransferase. (B) Female ANKO mice were given drinking water containing NMN (500 mg/kg-body weight/day). Adipose tissue NAD+ concentrations were determined in female ANKO mice after 4–6 weeks of treatment of NMN and untreated ANKO mice (n=5–7 per group). (C) ITTs were performed after 4 weeks of treatment of NMN. ITTs results from NMN-treated mice (n=7), age-matched 2- to 3- month-old untreated ANKO (n=14), and control mice (n=8) were shown. The AUC for glucose is shown next to the insulin tolerance curves. Plasma concentrations of insulin (D) and FFA (E) in NMN-treated, -untreated ANKO, and control mice (n=5–11 per group). Phosphorylated PPARγ (Ser273) (F), phosphorylated CDK5 (G), and lysine acetylation of nuclear proteins (H), in VAT obtained from NMN-treated and -untreated ANKO mice (n=3–4 per group). (I) VAT gene expression of obesity-liked PPARγ (Ser273) targets in NMN-treated and untreated ANKO mice (n=4–5 per group). (J) Plasma concentrations of adiponectin and adipsin in NMN-treated and -untreated ANKO mice (n=5–12 per group). Values are means ± SE. *,P < 0.05; **,P < 0.01; ***,P < 0.001 (NMN-tread ANKO vs. -untreated ANKO, Student’st test). a,P < 0.05 (NMN-treated vs. -untreated ANKO); b,P < 0.05 (control vs. NMN-untreated ANKO) (ANOVA).
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