Depletion of Alpha-Melanocyte-Stimulating Hormone Induces Insatiable Appetite and Gains in Energy Reserves and Body Weight in Zebrafish
The functions of anorexigenic neurons secreting proopiomelanocortin (POMC)/alpha-melanocyte-stimulating hormone (α-MSH) of the melanocortin system in the hypothalamus in vertebrates are energy homeostasis, food intake, and body weight regulation. However, the mechanisms remain elusive. This article...
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MDPI AG
2021-08-01
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| Online Access: | https://www.mdpi.com/2227-9059/9/8/941 |
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| author | Yang-Wen Hsieh Yi-Wen Tsai Hsin-Hung Lai Chi-Yu Lai Chiu-Ya Lin Guor Mour Her |
| author_facet | Yang-Wen Hsieh Yi-Wen Tsai Hsin-Hung Lai Chi-Yu Lai Chiu-Ya Lin Guor Mour Her |
| author_sort | Yang-Wen Hsieh |
| collection | DOAJ |
| description | The functions of anorexigenic neurons secreting proopiomelanocortin (POMC)/alpha-melanocyte-stimulating hormone (α-MSH) of the melanocortin system in the hypothalamus in vertebrates are energy homeostasis, food intake, and body weight regulation. However, the mechanisms remain elusive. This article reports on zebrafish that have been genetically engineered to produce α-MSH mutants, α-MSH<sup>−7aa</sup> and α-MSH<sup>−8aa</sup>, selectively lacking 7 and 8 amino acids within the α-MSH region, but retaining most of the other normal melanocortin-signaling (Pomc-derived) peptides. The α-MSH mutants exhibited hyperphagic phenotypes leading to body weight gain, as observed in human patients and mammalian models. The actions of several genes regulating appetite in zebrafish are similar to those in mammals when analyzed using gene expression analysis. These include four selected orexigenic genes: Promelanin-concentrating hormone (<i>pmch</i>), agouti-related protein 2 (<i>agrp2</i>), neuropeptide Y (<i>npy</i>), and hypothalamic hypocretin/orexin (<i>hcrt</i>). We also study five selected anorexigenic genes: Brain-derived neurotrophic factor (<i>bdnf</i>), single-minded homolog 1-a (<i>sim1a</i>), corticotropin-releasing hormone b (<i>crhb</i>), thyrotropin-releasing hormone (<i>trh</i>), and prohormone convertase 2 (<i>pcsk2</i>). The orexigenic actions of α-MSH mutants are rescued completely after hindbrain ventricle injection with a synthetic analog of α-MSH and a melanocortin receptor agonist, Melanotan II. We evaluate the adverse effects of MSH depletion on energy balance using the Alamar Blue metabolic rate assay. Our results show that α-MSH is a key regulator of POMC signaling in appetite regulation and energy expenditure, suggesting that it might be a potential therapeutic target for treating human obesity. |
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| language | English |
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| spelling | doaj.art-301853f67c3e4d84afa3048736c14a4d2023-11-22T06:52:18ZengMDPI AGBiomedicines2227-90592021-08-019894110.3390/biomedicines9080941Depletion of Alpha-Melanocyte-Stimulating Hormone Induces Insatiable Appetite and Gains in Energy Reserves and Body Weight in ZebrafishYang-Wen Hsieh0Yi-Wen Tsai1Hsin-Hung Lai2Chi-Yu Lai3Chiu-Ya Lin4Guor Mour Her5Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, TaiwanDepartment of Family Medicine, Chang Gung Memorial Hospital, Keelung 204, TaiwanInstitute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, TaiwanDepartment of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, TaiwanDepartment of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, TaiwanInstitute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, TaiwanThe functions of anorexigenic neurons secreting proopiomelanocortin (POMC)/alpha-melanocyte-stimulating hormone (α-MSH) of the melanocortin system in the hypothalamus in vertebrates are energy homeostasis, food intake, and body weight regulation. However, the mechanisms remain elusive. This article reports on zebrafish that have been genetically engineered to produce α-MSH mutants, α-MSH<sup>−7aa</sup> and α-MSH<sup>−8aa</sup>, selectively lacking 7 and 8 amino acids within the α-MSH region, but retaining most of the other normal melanocortin-signaling (Pomc-derived) peptides. The α-MSH mutants exhibited hyperphagic phenotypes leading to body weight gain, as observed in human patients and mammalian models. The actions of several genes regulating appetite in zebrafish are similar to those in mammals when analyzed using gene expression analysis. These include four selected orexigenic genes: Promelanin-concentrating hormone (<i>pmch</i>), agouti-related protein 2 (<i>agrp2</i>), neuropeptide Y (<i>npy</i>), and hypothalamic hypocretin/orexin (<i>hcrt</i>). We also study five selected anorexigenic genes: Brain-derived neurotrophic factor (<i>bdnf</i>), single-minded homolog 1-a (<i>sim1a</i>), corticotropin-releasing hormone b (<i>crhb</i>), thyrotropin-releasing hormone (<i>trh</i>), and prohormone convertase 2 (<i>pcsk2</i>). The orexigenic actions of α-MSH mutants are rescued completely after hindbrain ventricle injection with a synthetic analog of α-MSH and a melanocortin receptor agonist, Melanotan II. We evaluate the adverse effects of MSH depletion on energy balance using the Alamar Blue metabolic rate assay. Our results show that α-MSH is a key regulator of POMC signaling in appetite regulation and energy expenditure, suggesting that it might be a potential therapeutic target for treating human obesity.https://www.mdpi.com/2227-9059/9/8/941orexigenobesogensadipogenesishypothalamusappetite |
| spellingShingle | Yang-Wen Hsieh Yi-Wen Tsai Hsin-Hung Lai Chi-Yu Lai Chiu-Ya Lin Guor Mour Her Depletion of Alpha-Melanocyte-Stimulating Hormone Induces Insatiable Appetite and Gains in Energy Reserves and Body Weight in Zebrafish Biomedicines orexigen obesogens adipogenesis hypothalamus appetite |
| title | Depletion of Alpha-Melanocyte-Stimulating Hormone Induces Insatiable Appetite and Gains in Energy Reserves and Body Weight in Zebrafish |
| title_full | Depletion of Alpha-Melanocyte-Stimulating Hormone Induces Insatiable Appetite and Gains in Energy Reserves and Body Weight in Zebrafish |
| title_fullStr | Depletion of Alpha-Melanocyte-Stimulating Hormone Induces Insatiable Appetite and Gains in Energy Reserves and Body Weight in Zebrafish |
| title_full_unstemmed | Depletion of Alpha-Melanocyte-Stimulating Hormone Induces Insatiable Appetite and Gains in Energy Reserves and Body Weight in Zebrafish |
| title_short | Depletion of Alpha-Melanocyte-Stimulating Hormone Induces Insatiable Appetite and Gains in Energy Reserves and Body Weight in Zebrafish |
| title_sort | depletion of alpha melanocyte stimulating hormone induces insatiable appetite and gains in energy reserves and body weight in zebrafish |
| topic | orexigen obesogens adipogenesis hypothalamus appetite |
| url | https://www.mdpi.com/2227-9059/9/8/941 |
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