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Published on: May 24, 2018
Cotadutide (GLP-1/Glucagon dual receptor agonist) modulates hypothalamic orexigenic and anorexigenic neuropeptides in
Renata Spezani1, Thatiany Souza Marinho1, Thiago Santos Reis1
1Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Institute of Biology, Biomedical Center, The University of the State of Rio de Janeiro, Brazil.
Abstract:
The hypothalamic neuropeptides linked to appetite and satiety were investigated in obese mice treated with cotadutide (a dual receptor agonist of glucagon-like peptide 1 (GLP-1R)/Glucagon (GCGR)). Twelve-week-old male C57BL/6 mice were fed a control diet (C group, n = 20) or a high-fat diet (HF group, n = 20) for ten weeks. Each group was further divided, adding cotadutide treatment and forming groups C, CC, HF, and HFC for four additional weeks. The hypothalamic arcuate neurons were labeled by immunofluorescence, and protein expressions (Western blotting) for neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related protein (AgRP), and cocaine- and amphetamine-regulated transcript (CART). Cotadutide enhanced POMC and CART neuropeptides and depressed NPY and AGRP neuropeptides. In addition, gene expressions (RT-qPCR) determined that Lepr (leptin receptor) and Calcr (calcitonin receptor) were diminished in HF compared to C but enhanced in CC compared to C and HFC compared to HF. Besides, Socs3 (suppressor of cytokine signaling 3) was decreased in HFC compared to HF, while Sst (somatostatin) was higher in HFC compared to HF; Tac1 (tachykinin 1) and Mc4r (melanocortin-4-receptor) were lower in HF compared to C but increased in HFC compared to HF. Also, Glp1r and Gcgr were higher in HFC compared to HF. In conclusion, the findings are compelling, demonstrating the effects of cotadutide on hypothalamic neuropeptides and hormone receptors of obese mice. Cotadutide modulates energy balance through the gut-brain axis and its associated signaling pathways. The study provides insights into the mechanisms underlying cotadutide's anti-obesity effects and its possible implications for obesity treatment.
Insights
Cotadutide, a dual GLP-1R/GCGR agonist, impacts hypothalamic appetite signals in obese mice. It enhances satiety neuropeptides and alters hormone receptor expression, suggesting potential for obesity treatment via the gut-brain axis.
Area of Science:
- Neuroendocrinology
- Obesity Research
- Pharmacology
Background:
- Obesity is linked to dysregulated hypothalamic neuropeptides controlling appetite and satiety.
- Understanding the central mechanisms of anti-obesity drugs is crucial for effective treatment strategies.
Purpose of the Study:
- To investigate the effects of cotadutide, a dual glucagon-like peptide 1 receptor (GLP-1R)/Glucagon (GCGR) agonist, on hypothalamic neuropeptides and hormone receptors in diet-induced obese mice.
- To elucidate the mechanisms by which cotadutide modulates energy balance through the gut-brain axis.
Main Methods:
- Obese mice models were established using a high-fat diet.
- Cotadutide treatment was administered to assess its impact on hypothalamic neuropeptide (NPY, POMC, AgRP, CART) and hormone receptor (Lepr, Calcr, Socs3, Sst, Tac1, Mc4r, Glp1r, Gcgr) expression.
- Immunofluorescence and Western blotting were used for protein expression analysis; RT-qPCR was used for gene expression analysis.
Main Results:
- Cotadutide treatment enhanced proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) neuropeptides while reducing neuropeptide Y (NPY) and agouti-related protein (AgRP).
- Gene expression analysis revealed significant alterations in leptin receptor (Lepr), calcitonin receptor (Calcr), suppressor of cytokine signaling 3 (Socs3), somatostatin (Sst), tachykinin 1 (Tac1), melanocortin-4-receptor (Mc4r), Glp1r, and Gcgr following cotadutide treatment in obese mice.
- Cotadutide modulated key signaling pathways involved in energy homeostasis and appetite regulation.
Conclusions:
- Cotadutide effectively modulates hypothalamic neuropeptides and hormone receptors in obese mice.
- The drug influences energy balance by acting on the gut-brain axis and associated signaling pathways.
- These findings provide mechanistic insights into cotadutide's anti-obesity effects and highlight its therapeutic potential for obesity management.
