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. 2014 Nov;20(11):1263-9.
doi: 10.1038/nm.3699. Epub 2014 Oct 5.

Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice

Hanlin Tao  1 , Yong Zhang  1 , Xiangang Zeng  2 , Gerald I Shulman  3 , Shengkan Jin  1
Affiliations

Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice

Hanlin Tao et al. Nat Med. 2014 Nov.

Abstract

Type 2 diabetes (T2D) has reached an epidemic level globally. Most current treatments ameliorate the hyperglycemic symptom of the disease but are not effective in correcting its underlying cause. One important causal factor of T2D is ectopic accumulation of lipids in metabolically sensitive organs such as liver and muscle. Mitochondrial uncoupling, which reduces cellular energy efficiency and increases lipid oxidation, is an appealing therapeutic strategy. The challenge, however, is to discover safe mitochondrial uncouplers for practical use. Niclosamide is an anthelmintic drug approved by the US Food and Drug Administration that uncouples the mitochondria of parasitic worms. Here we show that niclosamide ethanolamine salt (NEN) uncouples mammalian mitochondria at upper nanomolar concentrations. Oral NEN increases energy expenditure and lipid metabolism in mice. It is also efficacious in preventing and treating hepatic steatosis and insulin resistance induced by a high-fat diet. Moreover, it improves glycemic control and delays disease progression in db/db mice. Given the well-documented safety profile of NEN, our study provides a potentially new and practical pharmacological approach for treating T2D.

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Figures

Figure 1
Figure 1
NEN uncouples mitochondrial respiration and impacts on mouse energy metabolism. (a) Chemical structure of niclosamide ethanolamine salt (NEN, 5-chloro-salicyl-(2-chloro-4-nitro) anilide 2-aminoethanol salt). (b) Oxygen consumption assay of isolated mouse liver mitochondria, showing oxygen concentration continuously measured as the indicated respiration substrates and inhibitors added into the respiration system to the final concentrations: succinate, 5 mM; ADP, 125 nM; oligomycin, 5 μg·ml−1, NEN, 1 μM; KCN, 2 mM. (c) Cellular oxygen consumption assay of NIH-3T3 cells treated with vehicle (Control), 1 μM NEN (NEN), 5 μg·ml−1 oligomycin (Oligomycin), or both (NEN + oligomycin). (d) Mouse energy expenditure, p=0.01. (e) Mouse oxygen consumption (VO2), p<0.01. (f) Mouse carbon dioxide generation (VCO2), p=0.05. (g) Mouse respiration quotient, p < 0.001. (h) Mouse rectal temperature. For d, e, f, g and h, male C57BL/6 mice were fed with HFD (control) or same HFD with 1,500 ppm NEN (NEN) for 1 wk, n = 8 for all groups. Statistical test in d, e, f and g, one-way analysis of variance (ANOVA); in h, student t-test.
Figure 2
Figure 2
Oral NEN is effective in preventing and treating HFD-induced insulin resistance. (a) Fasting blood glucose concentration of male C57BL/6 mice fed with either HFD (Control) or HFD with 1,500 ppm NEN (NEN), measured at wk 8 on HFD diet. (b) Basal plasma insulin concentration of the mice, as defined in a, measured at wk 8. (c) Glucose tolerance assay, and (d) insulin sensitivity assay of the mice, as defined in a, performed at wk 10. (e) Plasma lactate concentration of the mice, as defined in a, measured at wk 16 under indicated conditions. (f) Body weight of the mice, as defined in a, measured at indicated time points. (g) Fasting blood glucose concentration of male C57BL/6J mice that were first fed with HFD for 16 wk, and then randomized into two groups fed either with HFD (Control), or HFD containing 1,500 ppm NEN (NEN). The time when NEN containing food was initiated is designated as wk 0. (h) Basal plasma insulin concentration of the mice, as defined in g, measured at wk 2. (i) Glucose tolerance assay, and (j) insulin sensitivity assay of the mice, as defined in g, performed at wk 3. n = 7 for all groups. Student t-test, *P < 0.05; **P < 0.01; ***P < 0.001; error bar, s.d.
Figure 3
Figure 3
Oral NEN improves glycemic control in db/db mice. (a) Fasting blood glucose concentration of db/db mice fed with either normal chow diet (control), or the same chow diet containing 1,500 ppm NEN (NEN), measured at indicated time points. (b) Basal plasma insulin concentration of the db/db mice as defined in a, measured at indicated time points. (c) Glycated hemoglobin A1c (HbA1c) level of the db/db mice as defined in a, measured at day 60. (d) Body weight of the db/db mice as defined in a, measured at indicated time points. (e) Daily food intake of the db/db mice as defined in a. n = 9 for all groups. Student t-test; *P < 0.05; ***P < 0.001; error bar, s.d.
Figure 4
Figure 4
Oral NEN is effective in preventing and reducing HFD- induced hepatic steatosis in mice. (a) Representative liver morphology; scale bar, 1 cm; and (b) weight of whole liver of male C57BL/6J mice fed with normal chow diet (Normal), or HFD (HFD), or HFD containing 1,500 ppm NEN (HFD+NEN) for 16 wk starting at 5 wk of age, n = 3. (c) Representative liver sections stained with hematoxylin and eosin (H & E) or with Oil Red O, as indicated, and (d) quantification of hepatic triglyceride content, normalized to tissue weight, of liver tissue samples from male C57BL/6J mice fed for 16 wk with normal chow diet (Normal), or HFD, or HFD containing 1,500 ppm NEN (NEN prevention), or first fed with HFD for 16 wk and then switched to HFD containing 1,500 ppm NEN for 4 wk (NEN reversal). For c and d, n = 7 for all groups; in H & E staining of c, upper panel scale bar, 200 μm; middle panel scale bar, 100 μm; lower panel scale bar, 50 μm; for Oil Red O staining sections, scale bar, 50 μm. Student t-test, *P < 0.05; ***P < 0.001, error bar, s.d.
Figure 5
Figure 5
Effect of NEN on cellular metabolism. (a) Relative intracellular ATP concentrations (left panel) and ADP/ATP ratio (right panel) in cultured HepG2 cells without NEN treatment (control) or treated with 1.0 μM NEN for 2 h (NEN). (b) Immunoblotting analyses of NIH-3T3 cells showing NEN activates AMPK in a dose- (left panel, 2 h, indicated concentrations of NEN) and time- (right panel, 1.0 μM NEN, indicated time points) dependent manner. (c) Immunoblotting analyses of the phosphorylation of AMPK and ACC in NIH-3T3 cells without treatment, or treated with 1.0 μM NEN alone, or treated with NEN in combination with AMPK inhibitor Compound C (CC) at indicated concentrations for 2 h. (d) Immunoblotting analyses of the phosphorylation of AMPK and ACC (left panel) and β-oxidation analyses (right panel) of HepG2 cells treated with or without 1.0 μM NEN for 2 h. (e) Immunoblotting analyses of AMPK phosphorylation in mouse liver from male C57BL/6J mice either fed with HFD (control) or HFD containing 1,500 ppm NEN (NEN) for overnight (left panel), or indicated period of time (right panel). (f) Immunoblotting analyses (left panel) and the quantifications (middle and right panels) of the expression and phosphorylation of ACC in liver samples from micefed for 8 wk HFD with or without NEN. p-AMPK, phosphorylated AMPK (Thr172); p-ACC, phosphorylated ACC (Ser79). Student t-test, **P < 0.01; ***P < 0.001, error bar, s.d.
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