Maternal Dietary Fat Determines Metabolic Profile and the Magnitude of Endocannabinoid Inhibition of the Stress Response in Neonatal Rat Offspring

D’Asti, Esterina; Hong, Liu; Tremblay‐Mercier, Jennifer; Grajzer, Magdalena; Cunnane, Stephen C.; Marzo, Vincenzo Di; Walker, Claire‐Dominique

doi:10.1210/en.2009-1092

Cited by 64 publications

(55 citation statements)

References 57 publications

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“…We also highlight that maternal dietary choices during pregnancy can program fetal pancreas development by altering eCB bioavailability (48,77), which prospectively determines the offspring's sensitivity to metabolic stressors. This observation has clinicopathological significance by pointing to an increased risk of diabetes in either malnourished or obese mothers and underpins the clinical potential of tissue-selective regulation of eCB levels.…”

Section: Discussionmentioning

confidence: 99%

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Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Malenczyk

Keimpema

Piscitelli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, endocannabinoids regulate cell proliferation, fate determination, and migration. Nevertheless, endocannabinoid contributions to the development of the endocrine pancreas remain unknown. Here, we show that α cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of β cells by CB 1 cannabinoid receptor (CB 1 R) engagement. Using subtractive pharmacology, we extend these findings to anandamide, a promiscuous endocannabinoid/endovanilloid ligand, which impacts both the determination of islet size by cell proliferation and α/β cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB 1 Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB 1 R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in ω-3 fatty acids during pregnancy and lactation in mice, which permanently reduces endocannabinoid levels in the offspring, phenocopies CB 1 R −/− islet microstructure and improves coordinated hormone secretion. Overall, our data mechanistically link endocannabinoids to cell proliferation and sorting during pancreatic islet formation, as well as to life-long programming of hormonal determinants of glucose homeostasis.A nandamide (AEA) and 2-arachydonoylglycerol (2-AG), major endocannabinoids (eCBs), are involved in the regulation of energy homeostasis through coordinated actions in peripheral organs (adipose tissue, liver, and pancreas) and brain (hypothalamus, ventral striatum) (1). eCB signals are particularly significant to coordinate the regulated release of insulin and glucagon from mature pancreatic islets (2-6). Genetic evidence from CB 1 cannabinoid receptor −/− (CB 1 R −/− ) mice supports these findings because CB 1 R −/− mice are lean, resistant to high fat diet-induced obesity and diabetes (4, 7-9). Whether eCBs impact the formation of the endocrine pancreas and predispose it to long-lasting changes in hormone release postnatally remains unknown.Because eCBs broadly affect cell proliferation, fate, motility, and differentiation (e.g., in sperm, hematopoietic and T cells, and neurons) (10-13), it is likely that they play a role in the cellular organization of developing pancreatic islets, possibly by affecting the spatial segregation of α and β cells. A contribution of eCBs to cell diversification and positioning in the developing pancreas is supported by the temporal control of their levels in fetal tissues (14) and circulation (15). Moreover, α and β cells in mature pancreatic islets express the molecular machinery for eCB metabolism together with CB 1 Rs and transient receptor potential cation channels, particularly subfamily V member 1 (TRPV1) (2,16,17). Understanding these developmental processes is also relevant to po...

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Section: Discussionmentioning

confidence: 99%

“…eCBs are derived from arachidonic acid (20:4), an ω-6 PUFA. Correspondingly, ω-3 PUFAenriched diet during pregnancy lowers 2-AG and AEA levels in the fetus (48). ω-3 PUFA intake is also beneficial for insulin secretion and sensitivity (49)(50)(51).…”

Section: -Ag Signaling Modulates β Cell Survival In Pancreatic Pseudmentioning

confidence: 98%

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Malenczyk

Keimpema

Piscitelli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…Thus, prenatal and postnatal exposure to restricted omega-3 diet has been associated to impaired endocannabinoid-mediated neuronal functions in the adult brain, together with behavioral abnormalities [36]. Moreover, exposure to a maternal diet rich in n-3 or n-6 fatty acids modifies arachidonic acid and/or endocannabinoid levels in neonatal hypothalamus and hippocampus, resulting in alterations in the hypothalamus- pituitary-adrenal axis functions [44]. Therefore, this piece of evidence suggests that an inadequate endocannabinoid signaling resulting from exposure to an unbalanced maternal diet, might disrupt the establishment of functional circuitries involved in metabolism, learning and emotional control, leading to metabolic and neurobehavioral abnormalities later in life [27].…”

Section: Introductionmentioning

confidence: 99%

A moderate diet restriction during pregnancy alters the levels of endocannabinoids and endocannabinoid-related lipids in the hypothalamus, hippocampus and olfactory bulb of rat offspring in a sex-specific manner

et al. 2017

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Undernutrition during pregnancy has been associated to increased vulnerability to develop metabolic and behavior alterations later in life. The endocannabinoid system might play an important role in these processes. Therefore, we investigated the effects of a moderate maternal calorie-restricted diet on the levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG), arachidonic acid (AA) and the N-acylethanolamines (NAEs) anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in the brain of newborn rat offspring. We focused on brain structures involved in metabolism, feeding behavior, as well as emotional and cognitive responses. Female Wistar rats were assigned during the entire pregnancy to either control diet (C) or restriction diet (R), consisting of a 20% calorie-restricted diet. Weight gain and caloric intake of rat dams were monitored and birth outcomes were assessed. 2-AG, AA and NAE levels were measured in hypothalamus, hippocampus and olfactory bulb of the offspring. R dams displayed lower gain weight from the middle pregnancy and consumed less calories during the entire pregnancy. Offspring from R dams were underweight at birth, but litter size was unaffected. In hypothalamus, R male offspring displayed decreased levels of AA and OEA, with no change in the levels of the endocannabinoids 2-AG and AEA. R female exhibited decreased 2-AG and PEA levels. The opposite was found in the hippocampus, where R male displayed increased 2-AG and AA levels, and R female exhibited elevated levels of AEA, AA and PEA. In the olfactory bulb, only R female presented decreased levels of AEA, AA and PEA. Therefore, a moderate diet restriction during the entire pregnancy alters differentially the endocannabinoids and/or endocannabinoid-related lipids in hypothalamus and hippocampus of the underweight offspring, similarly in both sexes, whereas sex-specific alterations occur in the olfactory bulb. Consequently, endocannabinoid and endocannabinoid-related lipid signaling alterations might be involved in the long-term and sexual dimorphism effects commonly observed after undernutrition and low birth weight.

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“…Few studies have investigated the effects of maternal obesity on stress reactivity, and those which have examined hypothalamic-pituitary-adrenal (HPA) axis reactivity have mainly reported short-term effects during development [8,9]. Importantly, Trottier et al [9] found that maternal hypernutrition blunts the stress response in neonatal pups while increasing stress reactivity during adolescence.…”

Section: Introductionmentioning

confidence: 99%

Prenatal Exposure to Maternal Obesity Alters Anxiety and Stress Coping Behaviors in Aged Mice

et al. 2015

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Background: There is growing evidence that maternal obesity and prenatal exposure to a high-fat diet program fetal development to regulate the physiology and behavior of the offspring in adulthood. Yet the extent to which the maternal dietary environment contributes to adult disease vulnerability remains unclear. In the current study we tested whether prenatal exposure to maternal obesity increases the offspring's vulnerability to stress-related psychiatric disorders. Methods: We used a mouse model of maternal diet-induced obesity to investigate whether maternal obesity affects the response to adult chronic stress exposure in young adult (3-month-old) and aged adult (12-month-old) offspring. Results: Long-lasting, delayed impairments to anxiety-like behaviors and stress coping strategies resulted on account of prenatal exposure to maternal obesity. Although maternal obesity did not change the offspring's behavioral response to chronic stress per se, we demonstrate that the behavioral outcomes induced by prenatal exposure to maternal obesity parallel the deleterious effects of adult chronic stress exposure in aged male mice. We found that the glucocorticoid receptor (GR, Nr3c1) is upregulated in various hypothalamic nuclei on account of maternal obesity. In addition, gene expression of a known regulator of the GR, FKBP51, is increased specifically within the paraventricular nucleus. Conclusions: These findings indicate that maternal obesity parallels the deleterious effects of adult chronic stress exposure, and furthermore identifies GR/FKBP51 signaling as a novel candidate pathway regulated by maternal obesity.

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Maternal Dietary Fat Determines Metabolic Profile and the Magnitude of Endocannabinoid Inhibition of the Stress Response in Neonatal Rat Offspring

Cited by 64 publications

References 57 publications

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

A moderate diet restriction during pregnancy alters the levels of endocannabinoids and endocannabinoid-related lipids in the hypothalamus, hippocampus and olfactory bulb of rat offspring in a sex-specific manner

Prenatal Exposure to Maternal Obesity Alters Anxiety and Stress Coping Behaviors in Aged Mice

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