Modulation of Sirt1 and FoxO1 on Hypothalamic Leptin-Mediated Sympathetic Activation and Inflammation in Diet-Induced Obese Rats

Autor: Hong Zheng, Xuefei Liu
Rok vydání: 2021
Předmět:
0301 basic medicine
Leptin
Male
medicine.medical_specialty
endocrine system
sympathetic nerve activity
Blotting
Western
Hypothalamus
FOXO1
Inflammation
030204 cardiovascular system & hematology
Diet
High-Fat
Rats
Sprague-Dawley
03 medical and health sciences
Mice
0302 clinical medicine
Sirtuin 1
obesity‐associated hypertension
Internal medicine
Medicine
Animals
energy‐sensing enzyme
Obesity
Cells
Cultured
Original Research
Mice
Knockout
business.industry
digestive
oral
and skin physiology
Sympathetic nerve activity
food and beverages
Rats
Disease Models
Animal
030104 developmental biology
Blood pressure
Endocrinology
Gene Expression Regulation
Gene Knockdown Techniques
Hypertension
RNA
lipids (amino acids
peptides
and proteins)
medicine.symptom
Cardiology and Cardiovascular Medicine
business
Energy Metabolism
Diet-induced obese
hormones
hormone substitutes
and hormone antagonists
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
Popis: Background Hypothalamic leptin‐mediated signaling contributes to the exaggerated sympatho‐excitation and increased blood pressure in obesity‐associated hypertension. The aim of the study was to investigate the roles of energy‐sensing enzyme sirtuin1 (Sirt1) and forkhead box protein O1 (FoxO1) on the hypothalamic leptin‐mediated high sympathetic nerve activity and inflammation in obesity. Methods and Results Sprague Dawley rats were fed with high‐fat diet (HFD) for 12 weeks. In vivo, the potential of Srit1 and FoxO1 in the sympathetic effects of leptin was investigated via siRNA injection to knockdown Sirt1 or FoxO1 gene in the arcuate nucleus (ARCN) of hypothalamus in rats. In vitro, the effects of Sirt1 or FoxO1 on leptin‐mediated inflammation were observed in proopiomelanocortin (POMC) and microglial cells. Knockdown Sirt1 by siRNA significantly reduced the renal sympathetic nerve activity (RSNA) and blood pressure responses to leptin injection in the ARCN in the HFD rats. Conversely, knockdown FoxO1 significantly enhanced the RSNA and blood pressure responses to leptin injection in the HFD rats. Knockdown Sirt1 reduced the levels of pro‐inflammatory cytokines interleukin 6 (IL‐6), tumor necrosis factor α (TNF‐α), interleukin 1β (IL‐1β), C1q/TNF‐related protein‐1 (CTRP1), and immune cell infiltration in the ARCN in the HFD rats. Knockdown FoxO1 significantly increased the level of IL‐6 in the ARCN of HFD rats. In cultured hypothalamic POMC and microglial cells, knockdown Sirt1 significantly reduced leptin‐induced IL‐6 expression, affected the levels of AMP‐activated protein kinase (AMPK) and serine/threonine‐specific protein kinase (Akt). Knockdown FoxO1 significantly increased leptin‐induced IL‐6 in both POMC cells and microglial cells. Conclusions These data suggest that both Sirt1 and FoxO1 are the key modulators of leptin signaling in the hypothalamus contributed to the over sympathetic activation and inflammation in obesity.
Databáze: OpenAIRE
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