5-aminolevulinic acid combined with ferrous ion reduces adiposity and improves glucose tolerance in diet-induced obese mice via enhancing mitochondrial function

Abstract

BackgroundMitochondrial dysfunction is associated with obesity and various obesity-associated pathological conditions including glucose intolerance. 5-Aminolevulinic acid (ALA), a precursor of heme metabolites, is a natural amino acid synthesized in the mitochondria, and various types of cytochromes containing heme contribute to aerobic energy metabolism. Thus, ALA might have beneficial effects on the reduction of adiposity and improvement of glucose tolerance through its promotion of heme synthesis. In the present study, we investigated the effects of ALA combined with sodium ferrous citrate (SFC) on obesity and glucose intolerance in diet-induced obese mice.MethodsWe used 20-weeks-old male C57BL/6J diet-induced obesity (DIO) mice that had been fed high-fat diet from 4th week or wild-type C57BL/6J mice. The DIO mice were orally administered ALA combined with SFC (ALA/SFC) for 6 weeks. At the 4th and 5th week during ALA/SFC administration, mice were fasted for 5 h and overnight, respectively and used for oral glucose tolerance test. After the ALA/SFC administration, the plasma glucose levels, weight of white adipose tissue, and expression levels of mitochondrial oxidative phosphorylation (OXPHOS) complexes were examined. Furthermore, the effects of ALA/SFC on lipid content and glucose uptake were examined in vitro.ResultsOral administration of ALA/SFC for 6 weeks reduced the body weight by about 10% and the weight of white adipose tissues in these animals. In vitro, ALA/SFC reduced lipid content in mouse 3T3-L1 adipocytes in a dose dependent manner, and enhanced glucose uptake in 3T3-L1 adipocytes by 70–90% and rat L6 myoblasts by 30% at 6 h. Additionally, oral administration of ALA/SFC reduced plasma glucose levels and improved glucose tolerance in DIO mice. Furthermore, ALA/SFC enhanced the expression of OXPHOS complexes III, IV, and V by 40–70% in white adipose tissues of DIO mice, improving mitochondrial function.ConclusionsOur findings indicate that ALA/SFC is effective in the reduction of adiposity and improvement of glucose tolerance, and that the induction of mitochondrial OXPHOS complex III, IV, and V by ALA/SFC might be an essential component of the molecular mechanisms underlying these effects. ALA/SFC might be a useful supplement for obesity and obesity-related metabolic disease such as type 2 diabetes mellitus.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-016-0108-3) contains supplementary material, which is available to authorized users.

Ablation of adipose-HO-1 expression increases white fat over beige fat through inhibition of mitochondrial fusion and of PGC1α in female mice

“…An increase of heme turnover following an increase of ALAS is associated with a reduction of adiposity, increased mitochondrial function and adipocyte function [56], [57]. These results are in agreement with this report that HO-1 deletion results in a decrease in heme turnover and PGC1α, the latter is essential to restore mitochondrial integrity and increase beige like cells.…”

Dietary 5-aminolevulinic acid enhances adenosine triphosphate production, ecdysis and immune response in Pacific white shrimp, Litopenaeus vannamei (Boone)

“…In mice, administration of 5‐ALA was previously reported to increase the ATP level in the liver (Ogura et al., ) and the expression and activity of respiratory cytochromes in the mitochondrial electron transport chain (Ogura et al., ; Ota et al., ). This result is similar to our current results in which the ATP level in the hepatopancreas of L. vannamei was higher in the 5‐ALA groups than in the control (Figure ), in a dose‐dependent manner.…”

“…Several studies of vertebrates and vertebrate cell lines support the hypothesis that exogenous 5‐ALA enhances haem synthesis and activity of haemoproteins: 5‐ALA administration (a) increased intracellular haem levels, increasing the activity of cytochrome P450 in vitro (Miura et al., ); (b) increased the activity of cytochrome c oxidase of the electron transport chain and raised ATP levels in mouse liver (Ogura et al., ); (c) enhanced protein expression of mitochondrial complexes III–V in mouse adipose tissue (Ota et al., ); (d) induced REV‐ERBα expression (Yamashita et al., ); and (e) induced both protein and mRNA expression of haem oxygenase‐1 (HO‐1) (a rate‐limiting enzyme in haem degradation) (Nishio et al., : Ito et al., ). 5‐aminolevulinic acid was also reported to enhance the immune response in chickens (Sato et al., ) and pigs (Chen et al., ) and improves growth performance in eels (Yasumoto, Miyanari, Yoshimura, Kondo & Takahashi, ) (although there is some disagreement on the effect of 5‐ALA on growth; see below).…”

“…Several studies of vertebrates and vertebrate cell lines support the hypothesis that exogenous 5-ALA enhances haem synthesis and activity of haemoproteins: 5-ALA administration (a) increased intracellular haem levels, increasing the activity of cytochrome P450 in vitro (Miura et al, 2015); (b) increased the activity of cytochrome c oxidase of the electron transport chain and raised ATP levels in mouse liver (Ogura et al, 2011); (c) enhanced protein expression of mitochondrial complexes III-V in mouse adipose tissue (Ota et al, 2017); (d) induced REV-ERBα expression (Yamashita et al, 2014);…”

Effects of 5-aminolevulinic acid and sodium ferrous citrate on fibroblasts from individuals with mitochondrial diseases

“…Since ALA causes tumour accumulation of protoporphyrin IX, it has already been used as an oral diagnostic drug for cancer in Japan, Europe, Australia, and Canada 2,3 . We previously reported that ALA supplementation in mice enhances cytochrome c oxidase (COX) activity and ATP production levels in liver, and ALA combined with sodium ferrous citrate (SFC) administration upregulates the expression of OXPHOS complexes III, IV, and V in white adipose tissues of diet-induced obese mice, resulting in reduced lipid content of adipocytes 4,5 . Furthermore, ALA combined with SFC in healthy humans increased the expression levels of haem oxygenase-1 (HO-1) in peripheral blood mononuclear cells, which has cytoprotective effects against oxidative stress and inflammation 6,7 .

Figure 1Haem biosynthesis pathway.

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