In humans and in experimental animals, administration of ciliary neurotrophic factor (CNTF) reduces food intake and body weight. Studies of animal models have consistently demonstrated that exogenous CNTF not only reduces food intake, by acting on hypothalamic and brainstem feeding centres, but also improves obesity-associated hyperglycaemia, hyperinsulinemia and hyperlipidaemia by exerting metabolic effects through actions on peripheral organs, including white adipose tissue, skeletal muscle and the liver. Very few data are yet available on a possible role of endogenous CNTF as a modulator of energy balance. In this project we tested whether endogenous CNTF might be involved in energy balance regulation by assessing the metabolic phenotype of CNTF ablated mice (CNTF-/-) fed normal chow diet (NCD) or an high-fat diet (HFD). The main results obtained were: 1) adult male CNTF-/- mice challenged with an HFD for 13 weeks gained significant more body weight than the littermate controls fed the HFD (WT); 2) when compared with the respective WT animals, NCD fed CNTF-/- mice exhibited a higher adipocyte hypertrophy in mesenteric and epididymal visceral white adipose tissue (WAT) depots whereas the HFD fed CNTF-/- mice showed increased macrophage infiltration and an higher proneness of adipocyte to death at these visceral WAT depots; 3) visceral WAT cellular derangements in the CNTF-/- mice matched with the overexpression of the monocyte chemoattractant protein 1 and the proinflammatory cytokine tumour necrosis α, whereas adiponectin expression was found to be reduced in the epididymal depot of HFD fed mice; 4) lack of CNTF in both NCD and HFD fed mice involved an impairment of insulin signalling in the skeletal muscle and in the liver where, in addiction, a massive steatosis was especially evident in the HFD fed CNTF-/- mice in comparison with the WT mice kept under the same nutritional conditions; 5) HFD fed CNTF-/- mice exhibited higher circulating insulin and HOMA index in comparison with their HFD fed controls. Collectively, these data suggest that endogenous CNTF, possibly produced and secreted in the blood by a/some yet unidentified cellular source/s may reach peripheral metabolically relevant organs that bear its specific receptor and exert metabolic effects under distinctive physiological or pathophysiological conditions.
Nell'uomo e negli animali da esperimento, la somministrazione del fattore neurotrofico ciliare (CNTF) riduce l'assunzione di cibo e il peso corporeo. Studi su modelli animali hanno costantemente dimostrato che il CNTF esogeno non solo riduce l'assunzione di cibo, agendo sui centri di alimentazione ipotalamica e del tronco encefalico, ma migliora anche l'iperglicemia, l'iperinsulinemia e l'iperlipidemia associate all'obesità esercitando effetti metabolici attraverso azioni sugli organi periferici, incluso il tessuto adiposo bianco, muscolo scheletrico e fegato. Pochissimi dati sono ancora disponibili su un possibile ruolo del CNTF endogeno come modulatore del bilancio energetico. In questo progetto abbiamo testato se il CNTF endogeno potrebbe essere coinvolto nella regolazione del bilancio energetico valutando il fenotipo metabolico dei topi in cui è stato deleto il CNTF (CNTF-/-) alimentati con la dieta normale (NCD) o una dieta ricca di grassi (HFD). I principali risultati ottenuti sono stati: 1) i topi CNTF-/- maschi adulti alimentati con HFD per 13 settimane hanno guadagnato un peso corporeo significativamente maggiore rispetto ai littermates alimentati con HFD (WT); 2) quando comparati con gli animali WT, i topi CNTF-/- nutriti con NCD hanno mostrato un'ipertrofia adipocitaria più elevata nei depositi di tessuto adiposo bianco viscerale mesenterico ed epididimale (WAT) mentre i topi CNTF-/- alimentati con HFD hanno mostrato una maggiore infiltrazione di macrofagi e una maggiore predisposizione alla morte degli adipociti in questi depositi WAT viscerali; 3) squilibri cellulari nel tessuto adiposo bianco viscerale nei topi CNTF-/- correlano con la sovraespressione della proteina MCP1 e alla citochina infiammatoria TNFα, mentre l'espressione dell’adiponectina si è ridotta nel deposito epididimale dei topi nutriti con HFD; 4) la mancanza di CNTF nei topi nutriti con NCD e HFD comportava una compromissione della segnalazione dell’insulina nel muscolo scheletrico e nel fegato dove, inoltre, una steatosi massiccia era particolarmente evidente nei topi CNTF-/- alimentati con HFD rispetto ai topi WT mantenuti nelle stesse condizioni nutrizionali; 5) I topi CNTF-/- alimentati con HFD hanno mostrato livelli di insulina circolanti e un indice HOMA più elevati rispetto ai loro controlli alimentati con HFD. Collettivamente, questi dati suggeriscono che il CNTF endogeno, possibilmente prodotto e secreto nel sangue da una/qualche fonte/i cellulare non ancora identificata, può raggiungere organi periferici rilevanti dal punto di vista metabolico che portano il suo recettore specifico ed esercitare effetti metabolici in condizioni fisiologiche o patofisiologiche distintive.
Metabolic characterization of the Ciliary Neurotrophic Factor knockout mouse: a preliminary study / DI MERCURIO, Eleonora. - (2020 Oct 29).
Metabolic characterization of the Ciliary Neurotrophic Factor knockout mouse: a preliminary study.
DI MERCURIO, ELEONORA
2020-10-29
Abstract
In humans and in experimental animals, administration of ciliary neurotrophic factor (CNTF) reduces food intake and body weight. Studies of animal models have consistently demonstrated that exogenous CNTF not only reduces food intake, by acting on hypothalamic and brainstem feeding centres, but also improves obesity-associated hyperglycaemia, hyperinsulinemia and hyperlipidaemia by exerting metabolic effects through actions on peripheral organs, including white adipose tissue, skeletal muscle and the liver. Very few data are yet available on a possible role of endogenous CNTF as a modulator of energy balance. In this project we tested whether endogenous CNTF might be involved in energy balance regulation by assessing the metabolic phenotype of CNTF ablated mice (CNTF-/-) fed normal chow diet (NCD) or an high-fat diet (HFD). The main results obtained were: 1) adult male CNTF-/- mice challenged with an HFD for 13 weeks gained significant more body weight than the littermate controls fed the HFD (WT); 2) when compared with the respective WT animals, NCD fed CNTF-/- mice exhibited a higher adipocyte hypertrophy in mesenteric and epididymal visceral white adipose tissue (WAT) depots whereas the HFD fed CNTF-/- mice showed increased macrophage infiltration and an higher proneness of adipocyte to death at these visceral WAT depots; 3) visceral WAT cellular derangements in the CNTF-/- mice matched with the overexpression of the monocyte chemoattractant protein 1 and the proinflammatory cytokine tumour necrosis α, whereas adiponectin expression was found to be reduced in the epididymal depot of HFD fed mice; 4) lack of CNTF in both NCD and HFD fed mice involved an impairment of insulin signalling in the skeletal muscle and in the liver where, in addiction, a massive steatosis was especially evident in the HFD fed CNTF-/- mice in comparison with the WT mice kept under the same nutritional conditions; 5) HFD fed CNTF-/- mice exhibited higher circulating insulin and HOMA index in comparison with their HFD fed controls. Collectively, these data suggest that endogenous CNTF, possibly produced and secreted in the blood by a/some yet unidentified cellular source/s may reach peripheral metabolically relevant organs that bear its specific receptor and exert metabolic effects under distinctive physiological or pathophysiological conditions.File | Dimensione | Formato | |
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