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. 2010 Apr;151(4):1622-32.
doi: 10.1210/en.2009-1019. Epub 2010 Feb 22.

Changes in melanocortin expression and inflammatory pathways in fetal offspring of nonhuman primates fed a high-fat diet

B E Grayson  1 , P R Levasseur, S M Williams, M S Smith, D L Marks, K L Grove
Affiliations

Changes in melanocortin expression and inflammatory pathways in fetal offspring of nonhuman primates fed a high-fat diet

B E Grayson et al. Endocrinology. 2010 Apr.

Abstract

The hypothalamic melanocortin system, which controls appetite and energy expenditure, develops during the third trimester in primates. Thus, maternal nutrition and health may have a profound influence on the development of this system. To study the effects of chronic maternal high-fat diet (HFD) on the development of the melanocortin system in the fetal nonhuman primate, we placed adult female macaques on either a control (CTR) diet or a HFD for up to 4 yr. A subgroup of adult female HFD animals was also switched to CTR diet during the fifth year of the study (diet reversal). Third-trimester fetuses from mothers on HFD showed increases in proopiomelanocortin mRNA expression, whereas agouti-related protein mRNA and peptide levels were decreased in comparison with CTR fetuses. Proinflammatory cytokines, including IL-1beta and IL-1 type 1 receptor, and markers of activated microglia were elevated in the hypothalamus, suggesting an activation of the local inflammatory response. Fetuses of diet-reversal mothers had normal melanocortin levels. These results raise the concern that chronic consumption of a HFD during pregnancy, independent of maternal obesity and diabetes, can lead to widespread activation of proinflammatory cytokines that may alter the development of the melanocortin system. The abnormalities in the fetal POMC system, if maintained into the postnatal period, could impact several systems, including body weight homeostasis, stress responses, and cardiovascular function. Indeed, the HFD offspring develop early-onset excess weight gain. These abnormalities may be prevented by healthful nutrient consumption during pregnancy even in obese and severely insulin-resistant individuals.

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Figures

Figure 1
Figure 1
Effects of mHFD on the fetal melanocortin system. A, Schematic of hypothalamic area. B and C, Representative low-power autoradiographic images of POMC in situ hybridization signal in the ARH in mCTR (B) and mHFD (C) G130 hypothalamus. Images correspond to bregma −06.75 mm according to the brain atlas (75). Scale bar, 1 mm. D, Maternal consumption of HFD caused 2-fold up-regulation of POMC mRNA in fetal ARH (n = 4–5; *, P < 0.05) (black, mCTR; white, mHFD). E–G, Representative fluorescent confocal micrographs of αMSH-ir in ARH in approximate location of red square on schematic in A. α-MSH-ir is low to undetectable (mCTR, E; mHFD, F) in the ARH and not evident in other projection areas (data not shown). Note adult α-MSH-ir is robust in G. H, Maternal consumption of HFD caused a decrease in AgRP mRNA and increase in MC4R mRNA expression in G130 offspring by real-time PCR of medial basal hypothalamic blocks (n = 4–7; *, P < 0.05) (black, mCTR; white, mHFD). I, Overall AgRP-ir in PVH is 6-fold higher in mCTR than mHFD (n = 4–5; *, P < 0.05) (black, mCTR; white, mHFD). J–L, Representative fluorescent confocal micrographs of AgRP-ir in the PVH in the general area denoted by green square in A. PVH is a terminal projection field for AgRP fibers from ARH. mCTR AgRP-ir (J) is greater than mHFD (K). Adult immunoreactivity (L) is shown for comparison. Scale bar, 100 μm.
Figure 2
Figure 2
mHFD causes activation of inflammatory response in the fetal hypothalamus. A–C, IL-1R1-ir in the ventromedial hypothalamus. A, Representative ×10 confocal fluorescent micrograph of IL-1R1-ir shown in region demarcated by the green square in C (yellow arrows, vascular endothelial cells; blue arrows, lateral ARH neurons). B, Representative ×40 confocal fluorescent micrograph of IL-1R1-ir. D–H, Iba1-ir in the fetal hypothalamus: D and E, Iba1-ir in the ARH of a mCTR offspring; F and G, Iba1-ir in the ARH of a mHFD offspring. A and C represent ×4 magnification images of the ARH. B and D represent ×10 magnification images of the ventromedial region of the ARH. The third ventricle is on the left edge of the image. H, Quantitative analysis of Iba1-ir area (left) and integrated OD (right). n= 4 per group; *, P < 0.05.
Figure 3
Figure 3
Effects of mDR on fetal POMC, AgRP, and cortisol. The mDR group is a cohort of animals that were maintained on the HFD for 4 yr and then switched back to the CTR just before the breeding season of the fifth year. A and B, Quantification of fetal in situ hybridization of POMC and AgRP mRNA; C, comparison of AgRP-ir fiber fluorescence; D, comparison of fetal cortisol measurements expressed in nanograms per milliliter (black, mCTR; gray, mDR).
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