Depleting hypothalamic somatostatinergic neurons recapitulates diabetic phenotypes in mouse brain, bone marrow, adipose and retina
© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature..
AIMS/HYPOTHESIS: Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of the metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunological pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation.
METHODS: The present data show that leptin receptor-deficient (db/db) mice exhibit reduced hypothalamic SST neurons, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus delivery of diphtheria toxin subunit A (DTA) driven by an SST-cre system to deplete these neurons in Sstcre/gfp mice (SST-DTA).
RESULTS: SST-DTA mice exhibit enhanced hypothalamic c-Fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed haematopoiesis, generating excess granulocyte-monocyte progenitors and increased proinflammatory (C-C chemokine receptor type 2; CCR2hi) monocytes. SST-DTA mice exhibited a 'diabetic retinopathy-like' phenotype: reduced visual function by optokinetic response (0.4 vs 0.25 cycles/degree; SST-DTA vs control mice); delayed electroretinogram oscillatory potentials; and increased percentages of retinal monocytes. Finally, mesenteric visceral adipose tissue from SST-DTA mice was resistant to catecholamine-induced lipolysis, displaying 50% reduction in isoprenaline (isoproterenol)-induced lipolysis compared with control littermates. Importantly, hyperglycaemia was not observed in SST-DTA mice.
CONCLUSIONS/INTERPRETATION: The isolated reduction in hypothalamic SST neurons was able to recapitulate several hallmark features of type 2 diabetes in disease-relevant tissues.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:64 |
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| Enthalten in: |
Diabetologia - 64(2021), 11 vom: 22. Nov., Seite 2575-2588 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Huang, Chao [VerfasserIn] |
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| Links: |
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| Themen: |
51110-01-1 |
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| Anmerkungen: |
Date Completed 25.03.2022 Date Revised 01.07.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00125-021-05549-6 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM329742051 |
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| 100 | 1 | |a Huang, Chao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Depleting hypothalamic somatostatinergic neurons recapitulates diabetic phenotypes in mouse brain, bone marrow, adipose and retina |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Revised 01.07.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. | ||
| 520 | |a AIMS/HYPOTHESIS: Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of the metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunological pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation | ||
| 520 | |a METHODS: The present data show that leptin receptor-deficient (db/db) mice exhibit reduced hypothalamic SST neurons, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus delivery of diphtheria toxin subunit A (DTA) driven by an SST-cre system to deplete these neurons in Sstcre/gfp mice (SST-DTA) | ||
| 520 | |a RESULTS: SST-DTA mice exhibit enhanced hypothalamic c-Fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed haematopoiesis, generating excess granulocyte-monocyte progenitors and increased proinflammatory (C-C chemokine receptor type 2; CCR2hi) monocytes. SST-DTA mice exhibited a 'diabetic retinopathy-like' phenotype: reduced visual function by optokinetic response (0.4 vs 0.25 cycles/degree; SST-DTA vs control mice); delayed electroretinogram oscillatory potentials; and increased percentages of retinal monocytes. Finally, mesenteric visceral adipose tissue from SST-DTA mice was resistant to catecholamine-induced lipolysis, displaying 50% reduction in isoprenaline (isoproterenol)-induced lipolysis compared with control littermates. Importantly, hyperglycaemia was not observed in SST-DTA mice | ||
| 520 | |a CONCLUSIONS/INTERPRETATION: The isolated reduction in hypothalamic SST neurons was able to recapitulate several hallmark features of type 2 diabetes in disease-relevant tissues | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Diabetes | |
| 650 | 4 | |a Electroretinogram | |
| 650 | 4 | |a Hypothalamus | |
| 650 | 4 | |a Monocytosis | |
| 650 | 4 | |a Neuroimmunology | |
| 650 | 4 | |a Retina | |
| 650 | 4 | |a Somatostatin | |
| 650 | 7 | |a Diphtheria Toxin |2 NLM | |
| 650 | 7 | |a Somatostatin |2 NLM | |
| 650 | 7 | |a 51110-01-1 |2 NLM | |
| 700 | 1 | |a Rosencrans, Robert F |e verfasserin |4 aut | |
| 700 | 1 | |a Bugescu, Raluca |e verfasserin |4 aut | |
| 700 | 1 | |a Vieira, Cristiano P |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Adu-Agyeiwaah, Yvonne |e verfasserin |4 aut | |
| 700 | 1 | |a Gamble, Karen L |e verfasserin |4 aut | |
| 700 | 1 | |a Longhini, Ana Leda F |e verfasserin |4 aut | |
| 700 | 1 | |a Fuller, Patrick M |e verfasserin |4 aut | |
| 700 | 1 | |a Leinninger, Gina M |e verfasserin |4 aut | |
| 700 | 1 | |a Grant, Maria B |e verfasserin |4 aut | |
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