2-Aminoadipic acid protects against obesity and diabetes

in Journal of Endocrinology
Correspondence should be addressed to Z-G Wang: zhugangw@shsmu.edu.cn

*(W-Y Xu, Y Shen and H Zhu contributed equally to this work)

Restricted access

Obesity and type 2 diabetes (T2D) are both complicated endocrine disorders resulting from an interaction between multiple predisposing genes and environmental triggers, while diet and exercise have key influence on metabolic disorders. Previous reports demonstrated that 2-aminoadipic acid (2-AAA), an intermediate metabolite of lysine metabolism, could modulate insulin secretion and predict T2D, suggesting the role of 2-AAA in glycolipid metabolism. Here, we showed that treatment of diet-induced obesity (DIO) mice with 2-AAA significantly reduced body weight, decreased fat accumulation and lowered fasting glucose. Furthermore, Dhtkd1−/− mice, in which the substrate of DHTKD1 2-AAA increased to a significant high level, were resistant to DIO and obesity-related insulin resistance. Further study showed that 2-AAA induced higher energy expenditure due to increased adipocyte thermogenesis via upregulating PGC1α and UCP1 mediated by β3AR activation, and stimulated lipolysis depending on enhanced expression of hormone-sensitive lipase (HSL) through activating β3AR signaling. Moreover, 2-AAA could alleviate the diabetic symptoms of db/db mice. Our data showed that 2-AAA played an important role in regulating glycolipid metabolism independent of diet and exercise, implying that improving the level of 2-AAA in vivo could be developed as a strategy in the treatment of obesity or diabetes.

Downloadable materials

  • Supplementary Fig. 1
  • Supplementary Fig. 2
  • Supplementary Fig. 3
  • Supplementary Fig. 4
  • Supplementary Fig. 5
  • Supplementary Fig. 6
  • Supplementary Fig. 7
  • Supplementary Fig. 8
  • Supplementary Fig. 9
  • Supplementary Fig. 10
  • Supplementary Fig. 11
  • Supplementary Fig. 12
  • Supplementary Fig. 13
  • Table S1. Specific primers for quantitative RT-PCR.

 

      Society for Endocrinology

Related Articles

Article Information

Metrics

All Time Past Year Past 30 Days
Abstract Views 271 271 137
Full Text Views 54 54 30
PDF Downloads 27 27 14

Altmetrics

Figures

  • View in gallery

    2-AAA intake protects mice against obesity. (A) Body weights of mice (n = 12 mice/group). (B) Photographs of mouse morphology and anatomical abdomen. (C) MRI analysis shows the contents of fat mass and lean mass (n = 5 mice/group). (D) Photographs of isolated adipose tissues, liver and kidney. (E) Isolated organ weights of mice (n = 5 mice/group). (F) HE staining of adipose tissues and oil-red staining of liver. Scale bar, 100 μm. (G) Serum leptin levels of mice (n = 8 mice/group). A full colour version of this figure is available at https://doi.org/10.1530/JOE-19-0157.

  • View in gallery

    Dhtkd1 deficiency protects mice against obesity. (A) Body weights of mice (n = 10 mice/group). (B) Photographs of anatomical abdomen of mice. (C) MRI analysis of the contents of fat mass and lean mass (n = 5 mice/group). (D) Photographs of isolated adipose tissues, liver and kidney. (E) Isolated organ weights of mice (n = 5 mice/group). (F) HE staining of adipose tissues and oil-red staining of liver. Scale bar, 100 μm. (G) Serum leptin levels of mice (n = 8 mice/group). A full colour version of this figure is available at https://doi.org/10.1530/JOE-19-0157.

  • View in gallery

    2-AAA administration promotes thermogenesis in BAT. (A) Body temperature changes of Dhtkd1−/− and wt mice upon cold (4°C) stress (n = 10 mice/group). (B) RNA expression of thermogenic genes in BAT from mice 4 h after 4°C exposure. (C) Western blot analysis in BAT from mice 4 h after 4°C exposure. (D) TEM pictures of BAT from Dhtkd1−/− and wt mice fed with HFD. Black arrows, mitochondria. Scale bar, 2 μm. (E) Ucp1 and Pgc1α RNA expression in BAT. (F) Western blot analysis in BAT from Dhtkd1−/− and wt mice fed with HFD. (G) Western blot analysis in BAT from 2-AAA-treated mice fed with HFD.

  • View in gallery

    2-AAA intake enhances lipolysis and browning of WAT via activating β3AR signaling. (A and B) mRNA expression of brown fat-specific genes in WAT. (C) Western blot analysis of lipolysis- and browning-related proteins in WAT. (D) mRNA expression in 3T3L1 cells upon 2-AAA treatment. (E) Western blot analysis of proteins in 3T3L1 cells upon 2-AAA treatment for 48 h. (F) mRNA expression of lipolysis-related genes in WAT.

  • View in gallery

    Both 2-AAA-treated and Dhtkd1-deficient mice show abnormal glucose metabolism induced by HFD. (A) Serum glucose levels of 2-AAA-treated mice fed with HFD (n = 10 mice/group). (B) Serum insulin levels of 2-AAA-treated mice fed with HFD (n = 10 mice/group). (C and D) GTT (C) and ITT (D) in 2-AAA-treated mice fed with HFD (n = 8 mice/group). (E) PAS staining of liver from 2-AAA-treated mice fed with HFD. Scale bar, 100 μm. (F) Serum glucose levels of Dhtkd1−/− and wt mice fed with HFD (n = 10 mice/group). (G) Serum insulin levels of Dhtkd1−/− and wt mice fed with HFD (n = 10 mice/group). (H and I) GTT (H) and ITT (I) in Dhtkd1−/− and wt mice fed with HFD (n = 8 mice/group). (J) TEM pictures of liver from Dhtkd1−/− and wt mice fed with HFD. Scale bar, 5 μm. (K) PAS staining of liver and muscle from Dhtkd1−/− and wt mice fed with HFD. Scale bar, 100 μm. A full colour version of this figure is available at https://doi.org/10.1530/JOE-19-0157.

  • View in gallery

    2-AAA ameliorates diabetes mellitus symptoms in db/db mice. (A) Body weights of 2-AAA-treated db/db mice (n = 9 mice/group). (B) MRI analysis of the contents of fat mass and lean mass in 2-AAA-treated db/db mice (n = 5 mice/group). (C) Organ weights of 2-AAA-treated and -untreated db/db mice (n = 5 mice/group). (D) Food and water consumption of 2-AAA-treated (3 weeks) and untreated db/db mice (n = 5 mice/group). (E) Serum glucose levels of 2-AAA-treated db/db mice (n = 9 mice/group). (F) Serum insulin levels of 2-AAA-treated db/db mice (n = 9 mice/group). (G) Hepatic glycogen of 2-AAA-treated db/db mice (n = 3 mice/group). (H and I) GTT (H) and ITT (I) in 2-AAA-treated db/db mice (n = 9 mice/group).

  • View in gallery

    Schematic representation of the potential mechanisms of DHTKD1 and 2-AAA in lipolysis. Loss of function of DHTKD1 causes obvious increase of 2-AAA level. Then accumulated 2-AAA overactivates β3AR signaling, leading to enhanced lipolysis and thermogenesis. A full colour version of this figure is available at https://doi.org/10.1530/JOE-19-0157.

PubMed

Google Scholar