Modulation of nutrient sensing nuclear hormone receptors promotes weight loss through appetite suppression in mice.
OBJECTIVE
Peroxisome proliferator activated receptors (PPARs) are nuclear receptors involved in glucose and lipid metabolism. Three isoforms of PPARs have been identified with different tissue distribution and biological functions. Although the pharmacology of each receptor is well studied, the physiological effect of simultaneous activation of PPARalpha, gamma and delta is only starting to emerge. We sought to determine the biological effects of a novel PPAR pan activator and elucidate the physiological mechanisms involved.


METHODS
Ob/ob, diet-induced obese (DIO) or PPARalpha knockout mice were administered a novel agonist that activates all PPARs to various degrees to determine the effect on body weight, body composition, food intake and energy expenditure. In addition, serum parameters including glucose, insulin, triglycerides and ketone bodies as well as tissue acylcarnitine were evaluated. The effect of the novel agonist on liver and skeletal muscle histopathology was also studied.


RESULTS
We report that simultaneous activation of all PPARs resulted in substantial weight loss in ob/ob and DIO mice. Consistent with known PPAR pharmacology, we observed that agonist treatment increased lipid oxidation, although appetite suppression was mainly responsible for the weight loss. Agonist-induced weight loss was completely absent in PPARalpha knockout mice suggesting that PPARalpha pharmacology was the major contributor to weight regulation in mice.


CONCLUSIONS
Our work provides evidence that simultaneous activation of PPARalpha, gamma and delta decreases body weight by regulating appetite. These effects of the pan agonist were completely absent in PPARalpha knockout mice, suggesting that PPARalpha pharmacology was the major contributor to weight loss.
Metabolic Disease and Hemophilia Research, Wyeth Research, Cambridge, MA 02140, USA. mperreault@wyeth.com
M
M
Perreault
S
S
Will
D
D
Panza
T
T
Gareski
K
K
Harding
D
D
Kubasiak
M
M
Jalenak
K
K
Gartrell
S
S
Wang
G
G
Bollag
D R
DR
Artis
P N
PN
Ibrahim
P
P
Womack
J J
JJ
Lin
E
E
Saiah
T S
TS
Mansour
G P
GP
Vlasuk
D V
DV
Erbe
J F
JF
Tobin
D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001069:Appetite Regulation / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy* / Q000503:physiopathology; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics; D047494:PPAR delta / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D015431:Weight Loss / Q000502:physiology*
D001067:Appetite Depressants; C425931:GW 501516; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone