Differential expression of hypothalamic neuropeptides in the early phase of diet-induced obesity in mice.
Exposure to high-fat diets for prolonged periods results in positive energy balance and obesity, but little is known about the initial physiological and neuroendocrine response of obesity-susceptible strains to high-fat feeding. To assess responses of C57BL/6J mice to high- and low-fat diets, we quantitated the hypothalamic expression of neuropeptides implicated in weight regulation and neuroendocrine function over a 2-wk period. Exposure to high-fat diet increased food consumption over a 2-day period during which leptin levels were increased when assessed by a frequent sampling protocol [area under the curve (AUC): 134.6 +/- 10.3 vs. 100 +/- 12.3, P = 0.03 during first day and 126.5 +/- 8.2 vs. 100 +/- 5.2, P = 0.02 during second day]. During this period, hypothalamic expression of neuropeptide Y (NPY) and agouti-related protein (AgRP) decreased by approximately 30 and 50%, respectively (P < 0.001). After 1 wk, both caloric intake and hypothalamic expression of NPY and AgRP returned toward baseline. After 2 wk, cumulative caloric intake was again higher in the high-fat group, and now proopiomelanocortin (POMC) was elevated by 76% (P = 0.01). This study demonstrates that high-fat feeding induces hyperphagia, hyperleptinemia, and transient suppression of orexigenic neuropeptides during the first 2 days of diet. The subsequent induction of POMC may be a second defense against obesity. Attempts to understand the hypothalamic response to high-fat feeding must examine the changes as they develop over time.
Ziotopoulou
M
M
Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Mantzoros
C S
CS
Hileman
S M
SM
Flier
J S
JS
D054369:Agouti-Related Protein; D000818:Animals; D019540:Area Under Curve; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D004041:Dietary Fats / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D002149:Energy Intake / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000097:blood; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009478:Neuropeptide Y / Q000096:biosynthesis / Q000235:genetics; D009479:Neuropeptides / Q000096:biosynthesis* / Q000235:genetics; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis / Q000235:genetics; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D009478:Neuropeptide Y; D009479:Neuropeptides; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D011333:Pro-Opiomelanocortin; D003345:Corticosterone