Abstract
Hypothalamus is central to food intake and satiety. Recent data unveiled the expression of N-methyl-D-aspartate receptors (NMDAR) on hypothalamic neurons and their interaction with GABAA and serotoninergic neuronal circuits. However, the precise mechanisms governing energy homeostasis remain elusive. Notably, in females, the consumption of progesterone-containing preparations, such as hormonal replacement therapy and birth control pills, has been associated with hyperphagia and obesity—effects mediated through the hypothalamus. To elucidate this phenomenon, we employed the progesterone-induced obesity model in female Swiss albino mice. Four NMDAR modulators were selected viz. dextromethorphan (Dxt), minocycline, d-aspartate, and cycloserine. Obesity was induced in female mice by progesterone administration for 4 weeks. Mice were allocated into 7 groups, group-1 as vehicle control (arachis oil), group-2 (progesterone + arachis oil), and group-3 as positive-control (progesterone + sibutramine); other groups were treated with test drugs + progesterone. Various parameters were recorded like food intake, thermogenesis, serum lipids, insulin, AST and ALT levels, organ-to-body weight ratio, total body fat, adiposity index, brain serotonin levels, histology of liver, kidney, and sizing of fat cells. Dxt-treated group has shown a significant downturn in body weight (p < 0.05) by a decline in food intake (p < 0.01), organ-to-liver ratio (p < 0.001), adiposity index (p < 0.01), and a rise in body temperature and brain serotonin level (p < 0.001). Dxt demonstrated anti-obesity effects by multiple mechanisms including interaction with hypothalamic GABAA channels and anti-inflammatory and free radical scavenging effects, improving the brain serotonin levels, and increasing insulin release from the pancreatic β-cells.
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Data Availability
Data are available with the corresponding author and will be provided as needed.
Abbreviations
- 5-HT:
-
5-Hydroxytryptamine
- AgRP:
-
Agouti-related protein
- Akt:
-
Protein kinase b (pkb)
- ARRIVE:
-
Animal Research: Reporting of In Vivo Experiments
- ALT:
-
Alanine transaminase
- AMPA:
-
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- ARC:
-
Arcuate nucleus
- AST:
-
Aspartate aminotransferase
- BAT:
-
Brown adipose tissue
- BMI:
-
Body mass index
- BMR:
-
Basal metabolic rate
- CART:
-
Cocaine- and amphetamine-related transcript
- Dxt:
-
Dextromethorphan
- EDTA:
-
Ethylenediaminetetraacetic acid
- FoxO1:
-
Factor forkhead box protein 1
- GABA:
-
Gamma-aminobutyric acid
- GABAA :
-
Gamma-aminobutyric acid channel A
- HCl:
-
Hydrochloric acid
- HDL:
-
High-density lipoprotein
- HRT:
-
Hormone replacement therapy
- IR’s:
-
Insulin receptors
- LDL:
-
Low-density lipoprotein
- MC4R:
-
Melanocortin 4 receptor
- NA:
-
Noradrenaline
- NMDA:
-
The N-methyl-D-aspartate
- NMDAR:
-
The N-methyl-D-aspartate receptor
- NYP:
-
Neuropeptide Y
- ObRb:
-
Leptin receptors
- PI3K:
-
Phosphoinositide 3-kinase
- POMC:
-
Proopiomelanocortin-expressing
- PVN:
-
Paraventricular nucleus
- Pyy:
-
Pancreatic peptide YY
- STAT3:
-
Signal transducer and activator of transcription 3
- TC:
-
Total cholesterol
- TG:
-
Triglycerides
- VLDL:
-
Very-low-density lipoprotein
- WAT:
-
White adipose tissue
- WHO:
-
World Health Organization
- α-MSH:
-
α-Melanocyte stimulating hormone
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Acknowledgements
The authors are thankful to the Research and Development department of the Raghavendra Institute of Pharmaceutical Education and Research, Anantapur, India, for providing the necessary facilities for the successful completion of work.
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V.R.C., H.C.: Conceptualization; Shabnam Sultana: Methodology, Ethical permission, animal care, and handling; S.S.S., Sudarshan Singh: Data analysis; R.M., Sudarshan Singh: Writing the first draft of the manuscript; HC, Sudarshan Singh: Writing—review and editing; VRC, HC: Supervision. All authors contributed equally and agreed to the submitted version of the manuscript.
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The present study was approved by the Institutional Animals Ethics Committee (Ref: IAEC/I/01/RIPER/2022) Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapur, India. The reported research has strictly followed the national guidelines (CPCSEA) for the research on the experiments animals.
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Shiromwar, S.S., Chidrawar, V.R., Singh, S. et al. Multi-faceted Anti-obesity Effects of N-Methyl-D-Aspartate (NMDA) Receptor Modulators: Central-Peripheral Crosstalk. J Mol Neurosci 74, 13 (2024). https://doi.org/10.1007/s12031-023-02178-z
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DOI: https://doi.org/10.1007/s12031-023-02178-z