Endocrinol Metab.  2022 Apr;37(2):221-232. 10.3803/EnM.2021.1237.

Stimulation of Alpha-1-Adrenergic Receptor Ameliorates Obesity-Induced Cataracts by Activating Glycolysis and Inhibiting Cataract-Inducing Factors

• Lee YJ
• Jang YN
• Kim HM
• Han YM
• Seo HS
• Eom Y
• Song Js
• Jeong JH
• Jung TW

• KMID: 2529214
• DOI: http://doi.org/10.3803/EnM.2021.1237

Abstract

Background
Obesity, the prevalence of which is increasing due to the lack of exercise and increased consumption of Westernized diets, induces various complications, including ophthalmic diseases. For example, obesity is involved in the onset of cataracts.
Methods
To clarify the effects and mechanisms of midodrine, an α1-adrenergic receptor agonist, in cataracts induced by obesity, we conducted various analytic experiments in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a rat model of obesity.
Results
Midodrine prevented cataract occurrence and improved lens clearance in OLETF rats. In the lenses of OLETF rats treated with midodrine, we observed lower levels of aldose reductase, tumor necrosis factor-α, and sorbitol, but higher levels of hexokinase, 5’-adenosine monophosphate-activated protein kinase-alpha, adenosine 5´-triphosphate, peroxisome proliferator-activated receptordelta, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, superoxide dismutase, and catalase.
Conclusion
The ameliorating effects of midodrine on cataracts in the OLETF obesity rat model are exerted via the following three mechanisms: direct inhibition of the biosynthesis of sorbitol, which causes cataracts; reduction of reactive oxygen species and inflammation; and (3) stimulation of normal aerobic glycolysis.

Keyword

Aerobic glycolysis; Cataract; Inflammation; Adrenergic alpha-1 receptor; Midodrine; Obesity

Figure

• 

  Fig. 1. Body weight, visceral fat weight, and levels of triglycerides, cholesterol, and glucose in blood from Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats. (A, B) Body weight and visceral fat weight were higher in the non-treated OLETF control group than in the LETO group. However, they were lower in the midodrine-treated groups. (C) Triglyceride (TG) levels were higher in the non-treated OLETF controls than in the LETO group. However, the levels were lower in the midodrine-treated groups. (D) High-density lipoprotein (HDL)-cholesterol levels was higher in the midodrine-treated groups than in the non-treated OLETF control group. (E) Low-density lipoprotein (LDL)-cholesterol levels showed only a trend to be higher in the non-treated OLETF control and midodrine-treated groups than in the LETO group. However, there were statistically significant differences among the three OLETF groups. (F) Fasting blood glucose concentrations were higher in the OLETF control group than in the LETO group. However, there were no significant differences between the OLETF control and midodrine-treated groups. (G, H) The oral glucose tolerance test (OGTT) results were not significantly different between the OLETF control and midodrine-treated groups before and after the start of the animal experiment. Although the OGTT results before the experiment were not significantly different between the non-treated OLETF and midodrine-treated groups, the results at the end of the experiment showed a tendency for the midodrine-treated groups to have lower levels than the non-treated OLETF control group. The results are expressed as mean±standard error of the mean (n=5 or 6). Values were statistically analyzed using the unpaired t-test and one-way analysis of variance. All experiments were repeated three times. Mido 0.3, midodrine 0.3 mg/kg/day; Mido 1.0, midodrine 1.0 mg/kg/day. aP<0.001 vs. LETO; bP<0.05 vs. non-treated OLETF; cP<0.01 vs. non-treated OLETF; dP<0.001 vs. non-treated OLETF; eP<0.05 non-treated OLETF vs. Mido 0.3 and Mido 1.0; fP<0.01 non-treated OLETF vs. Mido 0.3 and Mido 1.0; gP<0.001 non-treated OLETF vs. Mido 0.3 and Mido 1.0; hP<0.05 vs. Mido 1.0.

• 

  Fig. 2. The occurrence rate of cataracts (ORC) and lens transparancy in Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats. (A) The ORC and mean cortical and posterior opacities were higher in the non-treated OLETF control group than in the LETO normal control group; however, they were lower in the midodrine-treated groups. (B) Lens transparency was aggravated in the non-treated OLETF control group compared to that in the LETO normal control group. However, this change was ameliorated in the midodrine 0.3 mg/kg/day treatment group. The results are expressed as mean±standard error of the mean (n=8 to 12). Values were statistically analyzed using the unpaired t test and one-way analysis of variance. All experiments were repeated three times. aP<0.01 vs. LETO; bP<0.05 vs. non-treated OLETF.

• 

  Fig. 3. The concentrations of aldose reductase, sorbitol dehydrogenase, 5´-adenosine monophosphate-activated protein kinase alpha (AMPKα), hexokinase and adenosine 5´-triphosphate (ATP) in the lens, the concentration of tumor necrosis factor-α (TNFα) in serum, and the protein levels of peroxisome proliferator-activated receptor delta (PPARδ) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in eye tissues other than the lens from Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats. (A) The aldose reductase concentration in the lens was lower in the midodrine-treated groups than in the non-treated OLETF control group. (B) The decreased sorbitol dehydrogenase concentration in the lens in the non-treated OLETF control group was not changed by midodrine treatment. (C) The hexokinase concentration was lower in the lens in the non-treated OLETF control group than in the LETO normal control group, however, it was significantly higher in the midodrine 1.0 mg/kg/day treatment group. (D) The concentration of AMPKα (phosphorylated at the threonine 172 residue) in eye tissues other than the lens was significantly elevated in the midodrine 0.3 mg/kg/day treatment group. (E) The ATP concentration in the lens showed a tendency to be lower in the non-treated OLETF control than in the LETO normal control group; however, it was higher in the midodrine-treated groups. (F) The TNFα concentration in serum was higher in the non-treated OLETF control group than in the LETO normal control group; however, it was lower in the midodrine 0.3 mg/kg/day treatment group. (G) The catalase concentration in eye tissues other than the lens was lower in the non-treated OLETF control group than in the LETO normal control group; however, it was significantly higher in the midodrine-treated groups. (H) The sorbitol concentration in serum was higher in the non-treated OLETF control group than in the LETO normal control group; however, it was lower in midodrine 1.0 mg/kg/day treatment group. (I) The protein levels for PPARδ, PGC-1α, and superoxide dismutase (SOD) in eye tissues other than the lens were higher in the midodrine-treated groups. The results are expressed as mean±standard error of the mean (n=5 or 6). Values were statistically analyzed using the unpaired t test and one way analysis of variance (ANOVA). All experiments were repeated three times. Mido 0.3, midodrine 0.3 mg/kg/day; Mido 1.0, midodrine 1.0 mg/kg/day. aP<0.05 vs. LETO; bP<0.05 vs. non-treated OLETF; cP<0.01 vs. non-treated OLETF; dP<0.001 vs. non-treated OLETF; eP<0.05 non-treated OLETF vs. Mido 0.3 and Mido 1.0; fP<0.01 non-treated OLETF vs. Mido 0.3 and Mido 1.0; gP<0.001 non-treated OLETF vs. Mido 0.3 and Mido 1.0; hP<0.05 vs. Mido 1.0.

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  Fig. 4. Diagram presenting the hypothesis generated in the present study for the effects and mechanism of midodrine on obesity-induced cataracts. Midodrine can prevent and cure obesity-induced cataracts through the inhibition of the polyol pathway, inflammation, and reactive oxygen species (ROS) and the activation of oxidative glycolysis. Meaning of symbols: A blue arrow indicates activation, blue upward and horizontal lines indicate inhibition, a red upward arrow indicates elevation, and a red X indicates blocking. PPARδ, peroxisome proliferator-activated receptor delta; AMPK, 5´-adenosine monophosphate-activated protein kinase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; TCA, tricarboxylic acid cycle; ATP, adenosine 5´-triphosphate.

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