Sensitivity of the hypothalamic paraventricular nucleus to the locomotor-activating effects of neuromedin U in obesity.
Obesity is associated with a decrease in energy expenditure relative to energy intake. The decrease in physical activity associated with obesity in several species, including humans, contributes to decreased energy expenditure. Several hormones and neuropeptides that affect appetite also modulate physical activity, including neuromedin U (NMU), a peptide found in the gut and brain. We have demonstrated that NMU microinjected into the hypothalamic paraventricular nucleus (PVN) in rats increases the energy expenditure associated with physical activity, called non-exercise activity thermogenesis (NEAT). Here we examined whether obesity in rats is related to decreased sensitivity of the PVN to the locomotor-activating effect of NMU. Diet-induced obese (DIO) rats and lean, diet-resistant (DR) rats were given PVN microinjections of increasing doses of NMU both before and after 1 month on a high-fat diet. We found that NMU increases physical activity, energy expenditure, and NEAT in a dose-dependent manner in both DR and DIO rats, both before and after 1 month on the high-fat diet. Before high-fat feeding, the obesity-prone and lean rats showed similar levels of physical activity after intra-PVN microinjections of NMU. After 1 month of the high-fat diet, however, the obesity-resistant rats showed significantly more NMU-induced physical activity compared to the obese DIO rats. Taken together with previous studies, these results suggest that obesity may represent a state associated with decreased central sensitivity to neuropeptides such as NMU that increase physical activity and therefore energy expenditure.
Novak
Colleen M
CM
Mayo Clinic, Endocrine Research Unit, St Marys Hospital, Joseph 5-194, 200 1st St. SW, Rochester, MN 55905, USA. novak.colleen@mayo.edu
Zhang
Minzhi
M
Levine
James A
JA
D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D004041:Dietary Fats / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005526:Food, Formulated; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism* / Q000494:pharmacology; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D022722:Thermogenesis / Q000187:drug effects / Q000502:physiology*
D004041:Dietary Fats; D009479:Neuropeptides; C056900:neuromedin U
Am J Physiol Regul Integr Comp Physiol. 2004 Nov;287(5):R1110-5
15475504
Science. 2005 May 13;308(5724):1043-5
15845877
J Comp Neurol. 2001 May 7;433(3):312-34
11298358
Am J Physiol Regul Integr Comp Physiol. 2000 Jan;278(1):R231-7
10644644
Arch Pediatr Adolesc Med. 2003 Sep;157(9):882-6
12963593
Am J Physiol Regul Integr Comp Physiol. 2005 Apr;288(4):R981-6
15604298
Am J Physiol. 1999 Jun;276(6):R1569-78
10362733
J Neurosci. 1986 Oct;6(10):2908-14
3020187
Adv Data. 2004 Oct 27;(347):1-17
15544194
Am J Physiol Regul Integr Comp Physiol. 2002 Oct;283(4):R941-8
12228064
Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9888-93
17517647
Am J Physiol Endocrinol Metab. 2001 Oct;281(4):E670-5
11551842
Jpn J Physiol. 1998 Jun;48(3):211-4
9689151
Endocrinology. 2002 Nov;143(11):4227-34
12399416
J Biol Rhythms. 1999 Oct;14(5):364-77
10511004
JAMA. 2002 Oct 9;288(14):1723-7
12365955
Nat Neurosci. 2005 May;8(5):579-84
15856066
Endocrinology. 2002 Oct;143(10):3813-21
12239092
Am J Med. 1997 Mar;102(3):259-64
9217594
Anim Behav. 1998 Jul;56(1):11-27
9710457
Nature. 2000 Jul 6;406(6791):70-4
10894543
Nature. 1998 May 7;393(6680):72-6
9590691
Am J Physiol Regul Integr Comp Physiol. 2003 Jun;284(6):R1454-65
12560202
Prog Brain Res. 1996;111:241-52
8990919
J Neurosci Methods. 2005 Aug 15;146(2):191-7
16054509
J Nutr. 2005 May;135(5):1314-9
15867332
Am J Physiol Endocrinol Metab. 2006 Feb;290(2):E396-403
16188908
Am J Physiol. 1998 Aug;275(2):R478-84
9688683
Med Sci Sports Exerc. 2004 May;36(5):890-6
15126726
Am J Med. 1998 Aug;105(2):145-50
9727822
N Engl J Med. 2004 Dec 23;351(26):2694-703
15616204
Med Sci Sports Exerc. 2005 May;37(5):724-30
15870624
J Clin Endocrinol Metab. 2006 Dec;91(12):5057-63
16984985
Biochem Biophys Res Commun. 2000 Mar 5;269(1):41-5
10694474
J Neurosci. 1999 Jan 1;19(1):328-33
9870962
Science. 2005 Jan 28;307(5709):584-6
15681386
Neurosci Lett. 2005 Jul 22-29;383(1-2):99-104
15936519
Am J Physiol. 1986 Sep;251(3 Pt 2):R433-40
3529988
Am J Physiol. 1989 Mar;256(3 Pt 2):R766-71
2646957
Physiol Behav. 2003 Nov;80(2-3):273-9
14637226
J Biol Rhythms. 2004 Feb;19(1):58-67
14964704
Regul Pept. 2000 Aug 25;92(1-3):31-5
11024562
Biochem Biophys Res Commun. 2004 Oct 8;323(1):65-71
15351702
Physiol Behav. 2006 Jun 30;88(3):294-301
16787655
Psychopharmacology (Berl). 2004 Dec;177(1-2):1-14
15205870
Am J Physiol. 1998 Aug;275(2):R471-7
9688682
Arch Gerontol Geriatr. 2004 Jul-Aug;39(1):83-91
15158583
Biochem Biophys Res Commun. 2001 Nov 23;289(1):225-8
11708803
Endocrinology. 2005 Oct;146(10):4217-23
15976061
J Nutr. 1991 Jul;121(7):1075-80
2051227
Peptides. 2004 Mar;25(3):473-504
15134868
Am J Physiol Regul Integr Comp Physiol. 2002 Feb;282(2):R546-51
11792665
Obes Res. 2001 Nov;9 Suppl 4:228S-233S
11707546
J Biol Chem. 2000 Dec 15;275(50):39482-6
11010960
Am J Physiol Regul Integr Comp Physiol. 2004 Jan;286(1):R143-50
12958061
Am J Physiol Endocrinol Metab. 2004 Apr;286(4):E551-9
14656716
Brain Res Gene Expr Patterns. 2001 Aug;1(1):1-4
15018811
Endocrinology. 2004 Aug;145(8):3904-12
15117877
Stress. 2004 Jun;7(2):109-12
15512854
Nat Med. 2004 Oct;10(10):1067-73
15448684
Int J Obes (Lond). 2006 Sep;30(9):1322-31
16801931
Endocrinology. 2004 Oct;145(10):4645-52
15231700
Neuroscience. 1988 Jun;25(3):797-816
3405430
J Neuroendocrinol. 2004 Jul;16(7):612-9
15214864
Am J Physiol Endocrinol Metab. 2005 Aug;289(2):E301-5
16014357
Am J Physiol. 1996 Feb;270(2 Pt 2):R456-61
8779879
Physiol Behav. 1991 Sep;50(3):573-81
1801012
Int J Obes (Lond). 2006 May;30(5):782-6
16404406
Can J Physiol Pharmacol. 1990 Jan;68(1):17-27
2183917
Am J Physiol Regul Integr Comp Physiol. 2003 Nov;285(5):R1184-91
12855420
J Neurochem. 2003 Dec;87(5):1165-73
14622096
Behav Processes. 2005 Feb 28;68(2):165-72
15686826
Science. 1999 Jan 8;283(5399):212-4
9880251
J Biol Chem. 2000 Oct 20;275(42):32452-9
10899166
J Neurophysiol. 2003 Aug;90(2):843-50
12711715
Am J Physiol. 1997 Aug;273(2 Pt 2):R725-30
9277561
Neuroendocrinology. 1990 Nov;52(5):441-7
2177853
EMBO J. 2005 Jan 26;24(2):325-35
15635449
Am J Physiol Regul Integr Comp Physiol. 2005 Sep;289(3):R704-11
15879056
Am J Clin Nutr. 2003 Aug;78(2):209-14
12885699
J Neuroendocrinol. 2006 Aug;18(8):594-601
16867180
Endocrinology. 2002 Nov;143(11):4320-9
12399428
Neurosci Lett. 2005 Feb 1;374(1):69-72
15631899
Endocrine. 2001 Dec;16(3):201-6
11954664
Biochem Biophys Res Commun. 2004 May 21;318(1):156-61
15110767
J Endocrinol. 2005 Apr;185(1):151-64
15817836
JAMA. 2003 Apr 9;289(14):1785-91
12684356
Eur J Clin Nutr. 1991 Sep;45(9):419-30
1959514
Curr Opin Clin Nutr Metab Care. 2004 Nov;7(6):599-605
15534426
Behav Brain Res. 2004 Oct 5;154(2):511-7
15313040
Am J Physiol Regul Integr Comp Physiol. 2000 Oct;279(4):R1357-64
11004005
Nature. 1982 May 27;297(5864):331-3
6978997
Biochem Biophys Res Commun. 2003 Nov 28;311(4):954-8
14623274
Endocrinology. 1988 Jan;122(1):270-82
3335208
J Clin Invest. 1995 Mar;95(3):980-5
7883999
Biochem Biophys Res Commun. 2000 Oct 14;277(1):191-4
11027662
Am J Physiol Regul Integr Comp Physiol. 2006 Oct;291(4):R889-99
16763079
Physiol Behav. 2002 Nov;77(2-3):251-7
12419401