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Does chronic inhibition of brain endoplasmic reticulum (ER) stress alter metabolic and cardiovascular function in obese melanocortin‐4 deficient rat?
Author(s) -
Carmo Jussara M.,
Silva Alexandre A.,
Yoo Jung,
Moak Sydney P.,
Spradley Frank,
Hall John E.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.964.1
Subject(s) - medicine , endocrinology , melanocortin , melanocortin 4 receptor , blood pressure , endoplasmic reticulum , tauroursodeoxycholic acid , unfolded protein response , leptin , obesity , chemistry , receptor , biochemistry
The central nervous system (CNS) melanocortin system plays a key role in regulating metabolic function and in mediating obesity‐induced hypertension. Although, endoplasmic reticulum (ER) stress has been suggested to alter hypothalamic pathways that regulate food intake, body weight and blood pressure (BP), its role in mediating cardiovascular and metabolic dysfunction in obesity is still unclear. In this study we examined the role of brain ER stress in controlling blood pressure (BP) and metabolic functions in obese melanocortin‐4 receptor (MC4R) deficient rats. MC4R knockout (MC4R −/− , n=5) and control wild‐type Wistar Hannover rats (WT, n=5) were implanted with blood pressure (BP) telemetry transmitters and an intracerebroventricular (ICV) cannula was inserted into the third ventricle at 22 weeks of age. After 10 days of recovery, food intake, BP and HR were measured 24‐hrs/day. After stable baseline measurements for 4 days, tauroursodeoxycholic acid (TUDCA, 7mg/hr, ICV) was infused via osmotic minipump for 7 consecutive days to inhibit brain ER stress. At baseline, MC4R −/− rats ate 42% more food and were 41% heavier than WT rats. MAP was higher (118±1 vs. 111±1 mmHg) and HR was lower (332±3 vs. 353±4 bpm) in MC4R−/− rats. Inhibition of brain ER stress significantly decreased cumulative net food intake (−26+4 vs. −16+5 g) while causing no changes in blood glucose levels (WT: 97±2 vs. 95±4 and MC4R−/−: 109±4 vs.106± 6 mg/dl) or body weight (WT: 446±11 vs. 448±12 and MC4R−/−: 629±23 vs.631± 30 g). Inhibition of brain ER stress also did not alter BP in either group (3 and 2 mmHg) but increased HR (8±2 and 19±4 bpm), respectively, in WT and MC4R −/− rats. These results suggest that chronic inhibition of brain ER stress reduced appetite but did not alter body weight, blood glucose or BP in WT or MC4R −/− rats. Support or Funding Information (NHLBI‐PO1HL51971, NIGMS‐P20GM104357 and AHA SDG5680016)