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Obesity Amplifies the Sympathoexcitatory Response to Insulin in Male, but not Female, Rats: Role of Neuropeptide Y Inputs into the Paraventricular Nucleus
Author(s) -
Shi Zhigang,
Cassaglia Priscila A.,
Brooks Virginia L.
Publication year - 2017
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.31.1_supplement.691.9
Subject(s) - medicine , endocrinology , leptin , insulin , obesity , neuropeptide y receptor , neuropeptide , receptor
Obesity in males sensitizes the brain to the sympathoexcitatory effects of leptin. However, whether obesity similarly enhances insulin‐induced increases in sympathetic nerve activity (SNA) is unknown. Moreover, while females are resistant to obesity‐induced hypertension, whether the insulin SNA response is sexually dimorphic in obese animals has not been investigated. Therefore, to test the hypothesis that insulin‐induced SNA responses are exaggerated in obese male, but not female rats, we studied SD rats (~8 wks of age) fed a high fat diet (HFD, 33% kcal fat) for 4–6 wk. Both male and female rats diverged into obesity‐prone (OP; top tertile of weight gain) and obesity resistant (OR; bottom tertile of weight gain) groups. Male and female OP and OR rats, as well as control (CON) rats fed a standard diet, were anesthetized with urethane, instrumented with lumbar nerve electrodes and femoral arterial and venous cannulae. Two hr intracerebroventricular (icv) insulin infusions (100 μU/min) in males increased lumbar SNA (LSNA) significantly more (P<0.05) in OP (380±93 % control; n=5) compared to CON (150±16 % control; n=5) or OR (154±13 % control; n=7) rats. However, in females, icv insulin increased (P<0.05) LSNA in CON (to 171±14 % control; n=4) and OR (to 188±13 % control; n=4) rats, but not in OP (to 101±8 % control; n=4) rats. Infusions of artificial cerebrospinal fluid icv had no effects in any group. These results indicate that obesity amplifies the SNA response to insulin in males, but abolishes the response in females. Insulin increases SNA via release of α‐melanocyte stimulating hormone in the paraventricular nucleus (PVN), and this excitation requires simultaneous suppression of tonic inhibitory Neuropeptide Y (NPY) inputs into the PVN. Obesity has been shown to decrease hypothalamic NPY expression, at least in males. Therefore, we next tested if a reduction of tonic NPY SNA inhibition contributes to enhanced insulin responses in OP males, but if NPY inhibition is maintained in OP females. In males, bilateral PVN nanoinjection of the select NPY Y1 receptor antagonist BIBO3304 (NPY1x; 60 pmol/60 nL) increased (P<0.05) LSNA in CON rats (n=6) to 118±2 % control and in OR rats (n=6) to 115±3 % control, but was ineffective in OP rats (to 105±3 % control; n=6). In contrast, in females, PVN NPY1x increased (P<0.05) LSNA in all groups (to 120±5 % control, CON, n=4; 122±6 % control, OR, n=3; and 118±6 % control, OP, n=3). In conclusion, the increase in LSNA in response to icv insulin is amplified in male obese rats, but is abolished in female obese rats. Obesity‐induced suppression of the tonic sympathoinhibitory effects of PVN NPY in males, but not females, may contribute to this sex difference. Support or Funding Information NIH HL128181 and HL088552, AHA 12GRNT11550018 and 15POST23040042.