Potential Applications of Thyroid Hormone Derivatives in Obesity and Type 2 Diabetes: Focus on 3,5-Diiodothyronine (3,5-T2) in Psammomys obesus (Fat Sand Rat) Model
Abstract
:1. Introduction
2. Materials and Methods
2.1. Experimental Protocol Design
2.2. Diet Composition
- (i)
- Group I submitted on natural diet (ND): Thirty two P. obesus are strictly maintained ad libitum on ND. This ND group represents the diet-control P. obesus. This ND is composed by halophilic plants of the Chenopodiaceae family (Traganum nudatum, Salsola foetidia, Suaeda fructosa and Artriplex halimus species), freshly harvested in their native biotope [10]. The P. obesus subsists primarily or exclusively of these plants whose sap has a very high salt concentration [11]. The ND is characterized by a low caloric value [12].
- (ii)
- Group submitted on HED before randomization: one hundred twenty five P. obesus are maintained on laboratory synthetic chow pellets (Carfil Quality, Beyntellus, Belgium; https://www.carfil.be, accessed on 1 January 1982). This synthetic diet is intended for all experimental rodents but it is considered to be high-caloric diet (3.25 kcal/g of diet) compared to ND (0.40 kcal/g of diet) and hence, it is used to develop obesity and diabetes [13]. The HED contain: 47.4% carbohydrates, 25% proteins, 7.5% fat, with high energy carbohydrates (33.5% starch and 13.5% total sugar), fatty substances, vitamins, minerals. P. obesus HED-fed group are randomized into three subgroups according experimental protocol described in Figure 1: Group II or HED-controlled group: Thirty P. obesus continue to feed on HED without treatment or supplementation; Group III or 3,5-T2-treated group: Sixty-five P. obesus continue to feed on HED and submitted to a continuous and constant administration 3,5-T2 (3,5-diiodothyronine) pellet implant according subcutaneous technique (25 µg/100 g body weight/day) during 5 weeks. Group IV or Placebo-controlled group: Fifteen P. obesus continue to feed on HED and submitted to a continuous and constant administration of vehicle (isotonic saline solution 0.9% NaCl) according subcutaneous a placebo pellet implant. A placebo pellet was implanted at the same time as the P. obesus treated with 3,5-T2. In fact, 3,5-T2-treated group received the HED for 10 weeks and were subsequently treated for five weeks simultaneously with HED. The pharmacological dose of 25 µg 3,5-T2/100 g body weight (BW) was chosen after reviewing data from previous studies [14] which used 3,5-T2 as treatment and we have adapted for our study in gerbil P. obesus. Indeed, recent studies have shown that chronic treatment during 4 weeks with doses of 50 µg of 3,5-T2/100 g BW to male Rats HED pre-fed did not result in any thyrotoxic effect that might be of clinical relevance.
2.3. 3,5-Diiodothyronine Pellet Implantation Method
2.4. Oxygen Consumption, Energy Expenditure, Basal Metabolic Rate Measurement
2.5. Adipose Tissue Samples and Adiposity Index Estimation
2.6. Plasma and Hepatic Biochemical Analysis
2.7. Plasma Thyroid Hormones Assays
2.8. Hepatocytes Isolation Method
2.9. Intracellular Metabolic Fluxes Analysis
2.10. Assessment of Hepatic Intracellular Intermediary Metabolites
2.11. Determination of Oxygen Consumption Rates
2.12. Hepatic Protein, Glycogen and Lipids Determination
2.13. Statistical Analyses
3. Results
3.1. In Vivo Effects of 3,5-T2 Treatment on Plasma Thyroid Hormone Profile
3.2. In Vivo Effects of 3,5-T2 Treatment on Body Weight, Calorie Intake, Respiratory Quotient and Basal Metabolic Rate
3.3. In Vivo Effects of 3,5-T2 Treatment on Body Adipose Tissue Distribution
3.4. In Vivo Effects of 3,5-T2 Treatment on Plasma and Liver Metabolic Disorders
3.5. In Vitro Effects of 3,5-T2 Treatment on Oxygen Consumption, Hepatic Gluconeogenesis, Ketogenesis, Intracellular Intermediary Metabolites, and Cellular Redox-Phosphate Potential
4. Discussion
4.1. The First Point Is Linked to 3,5-T2 Treatment on Plasma Thyroid Hormone Profile
4.2. The Second Point Is Linked to 3,5-T2 Treatment on Body Weight, Calorie Intake, Oxygen Consumption, Respiratory Quotient and Basal Metabolic Rate
4.3. The Third Point Is Linked to 3,5-T2 Treatment on Body Adipose Tissue Distribution
4.4. The Fourth Point Is Linked to 3,5-T2 Treatment on Plasma and Liver Metabolic Disorders
4.5. The Fifth Point Is Linked to 3,5-T2 Treatment on Hepatic Gluconeogenesis, Ketogenesis, Intracellular Intermediary Metabolites, and Cellular Redox-Phosphate Potential
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Parameters/Groups | Group I | Group II | Group III | Group IV |
---|---|---|---|---|
ND-controlled | HED-controlled | HED-3,5-T2-treated | HED-Placebo | |
Body weight (g) | 81 ± 3 | 144 ± 10 *** | 108 ± 3 ***/¶¶¶ | 141 ± 7 *** |
Thyroid weight (mg) | 11.5 ± 1.32 | 10.7 ± 2.69 ns | 10.3 ± 1.18 ns/ns | 10.1 ± 1.47 ns |
Thyroid mass (% body wt) | 14.1 ± 0.44 | 7.43 ± 0.26 *** | 9.53 ± 0.39 ***/¶¶¶ | 7.16 ± 0.21 *** |
TSH (µIU/mL) | 1.63 ± 0.52 | 1.37 ± 0.17 ns | 1.19 ± 0.49 ns/ns | 1.46 ± 0.81 ns |
TT4 (ng/mL) | 29.4 ± 2.23 | 24.3 ± 4.11 ns | 23.9 ± 3.22 ns/ns | 23.7 ± 1.34 ns |
FT4 (pg/mL) | 3.88 ± 0.11 | 3.75 ± 0.57 ns | 3.71 ± 0.66 ns/ns | 3.79 ± 0.45 ns |
TT3 (ng/mL) | 0.661 ± 0.08 | 0.344 ± 0.07 *** | 0.362 ± 0.03 ***/ns | 0.377 ± 0.09 *** |
FT3 (pg/mL) | 1.92 ± 0.08 | 1.77 ± 0.07 ** | 1.10 ± 0.09 ***/¶¶¶ | 1.83 ± 0.02 ** |
3,5-T2 (pg/mL) | 0.30 ± 0.09 | 0.24 ± 0.07 ns | 0.51 ± 0.05 ***/¶¶¶ | 0.27 ± 0.08 ns |
FT3/FT4-ratio | 0.49 ± 0.07 | 0.47 ± 0.01 ns | 0.29 ± 0.03 ***/¶¶¶ | 0.48 ± 0.04 ns |
FT3/3,5-T2-ratio | 6.41 ± 0.88 | 7.37 ± 0.11 ns | 2.15 ± 0.18 ***/¶¶¶ | 6.77 ± 0.25 ns |
FT4/3,5-T2-ratio | 12.9 ± 1.22 | 15.6 ± 1.42 ** | 7.27 ± 1.32 ***/¶¶¶ | 14.1 ± 0.11 ** |
Parameters/Groups | Group I | Group II | Group III | Group IV |
---|---|---|---|---|
ND-controlled | HED-controlled | HED-3,5-T2-treated | HED-Placebo | |
Body weight (g) | 81 ± 3 | 144 ± 10 *** | 108 ± 3 ***/¶¶¶ | 141 ± 7 *** |
BMI (g/cm2) | 0.38 ± 0.01 | 0.49 ± 0.01 *** | 0.32 ± 0.03 ns/¶¶¶ | 0.47 ± 0.02 *** |
Caloric intake (Kcal/100g BW) | 43.5 ± 1.9 | 316 ± 11 *** | 534 ± 10 ***/¶¶¶ | 322 ± 17 *** |
Respiratory quotient | 0.913 ± 0.09 | 0.975 ± 0.03 ns | 0.753 ± 0.05 ***/¶¶¶ | 0.944 ± 0.07 ns |
BMR (mLO2/h/g BW) | 0.521 ± 0.02 | 0.643 ± 0.09 *** | 0.891 ± 0.05 ***/¶¶¶ | 0.675 ± 0.03 *** |
Glucose (mmol/L) | 3.21 ± 0.51 | 15.2 ± 1.04 *** | 3.88 ± 0.17 ns/¶¶¶ | 14.9 ± 1.82 *** |
HbA1c (mmol/mol) | 17.9 ± 0.65 | 68.2 ± 9.44 *** | 20.5 ± 3.85 ns/¶¶¶ | 65.3 ± 7.11 *** |
Insulin (pmol/L) | 130 ± 21 | 580 ± 47 *** | 110 ± 14 ***/¶¶¶ | 608 ± 85 *** |
HOMA-IR | 2.57 ± 0.14 | 5.33 ± 0.23 *** | 2.68 ± 0.11 ns/¶¶¶ | 5.58 ± 0.44 *** |
ALT (IU/L) | 26.3 ± 1.58 | 74.1 ± 2.35 *** | 23.9 ± 1.47 ns/¶¶¶ | 81.3 ± 1.71 *** |
Triglycerides (mmol/L) | 0.81 ± 0.07 | 4.09 ± 0.61 *** | 1.58 ± 0.01 ***/¶ | 3.07 ± 0.06 *** |
Total cholesterol (mmol/L) | 1.48 ± 0.70 | 8.06 ± 1.22 *** | 2.81 ± 0.64 ***/¶¶¶ | 7.98 ± 1.15 *** |
NEFA (μmol/L) | 291 ± 33 | 578 ± 41 *** | 898 ± 66 ***/¶¶¶ | 609 ± 23 *** |
Ketone bodies (µmol/L) | 250 ± 16 | 303 ± 30 *** | 588 ± 57 ***/¶¶¶ | 278 ± 21 *** |
Lactate (mM) | 0.65 ± 0.09 | 1.13 ± 0.25 *** | 0.73 ± 0.14 ***/¶¶¶ | 1.05 ± 0.03 *** |
Parameters/Groups | Group I | Group II | Group III | Group IV |
---|---|---|---|---|
ND-controlled | HED-controlled | HED-3,5-T2-treated | HED-Placebo | |
Total visceral fat (mg/g BW) | 10.3 ± 3.38 | 25.8 ± 4.32 *** | 10.1 ± 1.85 ***/¶¶¶ | 26.3 ± 4.38 *** |
Retroperitoneal fat (mg/g BW) | 2.75 ± 0.66 | 3.02 ± 0.57 ns | 2.11 ± 0.44 ns/ns | 2.98 ± 0.75 ns |
Omental fat (mg/g BW) | 1.27 ± 0.91 | 9.95 ± 1.33 *** | 2.79 ± 0.68***/¶¶¶ | 10.1 ± 2.22 *** |
Mesenteric fat (mg/g BW) | 6.33 ± 1.81 | 12.9 ± 2.42 *** | 5.18 ± 0.73 ***/¶¶¶ | 13.2 ± 1.41 *** |
Epididymal fat (mg/g BW) | 3.14 ± 0.72 | 8.69 ± 1.47 *** | 2.25 ± 0.65 *** | 9.02 ± 0.73 *** |
Subcutaneous fat (mg/g BW) | 1.93 ± 0.17 | 8.33 ± 1.18 *** | 2.09 ± 0.15 ***/¶¶¶ | 7.92 ± 0.22 *** |
Perirenal fat (mg/g BW) | 2.13 ± 0.51 | 2.82 ± 1.61 ns | 2.03 ± 0.34 ns/ns | 2.57 ± 1.91 ns |
Suprascapular fat (mg/g BW) | 5.91 ± 2.14 | 12.5 ± 1.08 ** | 4.11 ± 1.33 ***/¶¶¶ | 11.9 ± 2.01 ** |
Gonadal fat (mg/g BW) | 1.78 ± 0.61 | 1.93 ± 0.22 ns | 1.66 ± 0.55 ns/ns | 1.86 ± 1.24 ns |
Intramuscular fat (mg/g BW) | 2.51 ± 0.33 | 3.74 ± 0.27 ** | 1.81 ± 0.24 ***/¶¶¶ | 3.67 ± 0.45 ** |
Adiposity index (% BW) | 2.61 ± 0.35 | 3.87 ± 0.95 *** | 1.07 ± 0.13 **/¶¶¶ | 3.91 ± 0.47 *** |
Brown adipose tissue (mg/g BW) | 0.46 ± 0.03 | 0.33 ± 0.07 * | 0.55 ± 0.05 */¶ | 0.31 ± 0.02 * |
Total hepatic lipids (g 100 g wet/wt) | 2.97 ± 0.31 | 6.17 ± 0.94 *** | 3.19 ± 0.11 ***/¶¶¶ | 5.83 ± 0.76 *** |
Hepatic glycogen (g/100 g wet/wt) | 2.77 ± 0.84 | 2.44 ± 0.93 * | 1.18 ± 0.02 ***/¶¶¶ | 2.65 ± 0.79 |
Liver mass (% body BW) | 2.51 ± 0.45 | 4.05 ± 0.78 *** | 2.89 ± 0.33 ***/¶¶¶ | 3.64 ± 1.49 *** |
Metabolic Fluxes (µmol/min/g Dry Cells) | Energy Substrates (mM) | Group I ND-Controlled | Group II HED-Controlled | Group III HED-3,5-T2-Treated | Group IV HED-Placebo | ||
---|---|---|---|---|---|---|---|
10−9 M 3,5-T2 | 10−6 M 3,5-T2 | 10−9 M 3,5-T2 | 10−6 M 3,5-T2 | ||||
Glucose synthesis | Ala+Octa | 4.33 ± 0.22 | 8.38 ± 0.54 | 2.55 ± 0.31 ***/¶¶¶ | 2.19 ± 0.11 ***/¶¶¶ | 4.22 ± 0.62 | 3.87 ± 0.22 |
(L+P)+Octa | 5.66 ± 0.31 | 12.1 ± 0.27 | 4.87 ± 0.17 ***/¶ | 2.66 ± 0.33 ***/¶¶¶ | 5.33 ± 0.41 | 5.02 ± 0.77 | |
Glycolysis | Ala+Octa | 1.83 ± 0.12 | 3.27 ± 0.14 | 1.65 ± 0.41 ***/¶¶¶ | 1.09 ± 0.53 ***/¶¶¶ | 2.02 ± 0.33 | 2.11 ± 0.12 |
Ketogenesis | Ala+Octa | 4.77 ± 0.33 | 5.65 ± 0.61 | 5.87 ± 0.55 ***/¶¶ | 6.29 ± 0.11 ***/¶¶¶ | 4.08 ± 0.34 | 3.95 ± 0.61 |
(L+P)+Octa | 3.76 ± 0.51 | 4.61 ± 0.37 | 4.97 ± 0.11 ***/¶ | 5.44 ± 0.13 ***/¶¶¶ | 3.05 ± 0.21 | 3.02 ± 0.17 | |
G6P (nmol/g dry cells) | 184 ± 62 | 227 ± 51 | 108 ± 31 ***/¶¶¶ | 97 ± 14 ***/¶¶¶ | 172 ± 23 | 181 ± 55 | |
F6P (nmol/g dry cells) | 299 ± 24 | 338 ± 55 | 317 ± 11 ***/¶¶¶ | 379 ± 19 ***/¶¶¶ | 304 ± 31 | 310 ± 22 | |
3PG (nmol/g dry cells) | 951 ± 16 | 1331 ± 77 | 1016 ± 33 ***/¶¶¶ | 1287 ± 46 ***/¶¶¶ | 997 ± 32 | 1008 ± 57 | |
PEP (μmol/g dry cells) | 575 ± 30 | 805 ± 44 | 895 ± 41 ***/¶¶¶ | 1034 ± 27 ***/¶¶¶ | 609 ± 22 | 645 ± 18 |
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Bouazza, A.; Favier, R.; Fontaine, E.; Leverve, X.; Koceir, E.-A. Potential Applications of Thyroid Hormone Derivatives in Obesity and Type 2 Diabetes: Focus on 3,5-Diiodothyronine (3,5-T2) in Psammomys obesus (Fat Sand Rat) Model. Nutrients 2022, 14, 3044. https://doi.org/10.3390/nu14153044
Bouazza A, Favier R, Fontaine E, Leverve X, Koceir E-A. Potential Applications of Thyroid Hormone Derivatives in Obesity and Type 2 Diabetes: Focus on 3,5-Diiodothyronine (3,5-T2) in Psammomys obesus (Fat Sand Rat) Model. Nutrients. 2022; 14(15):3044. https://doi.org/10.3390/nu14153044
Chicago/Turabian StyleBouazza, Asma, Roland Favier, Eric Fontaine, Xavier Leverve, and Elhadj-Ahmed Koceir. 2022. "Potential Applications of Thyroid Hormone Derivatives in Obesity and Type 2 Diabetes: Focus on 3,5-Diiodothyronine (3,5-T2) in Psammomys obesus (Fat Sand Rat) Model" Nutrients 14, no. 15: 3044. https://doi.org/10.3390/nu14153044