Abstract
Maternal malnutrition causes long-lasting alterations in feeding behavior and energy homeostasis in offspring. It is still unknown whether both, the endocannabinoid (eCB) machinery and the lipid metabolism are implicated in long-term adaptive responses to fetal reprogramming caused by maternal undernutrition. We investigated the long-term effects of maternal exposure to a 20% standard diet restriction during preconceptional and gestational periods on the metabolically-relevant tissues hypothalamus, liver, and perirenal fat (PAT) of male and female offspring at adulthood. The adult male offspring from calorie-restricted dams (RC males) exhibited a differential response to the CB1 antagonist AM251 in a chocolate preference test as well as increased body weight, perirenal adiposity, and plasma levels of triglycerides, LDL, VLDL, bilirubin, and leptin. The gene expression of the cannabinoid receptors Cnr1 and Cnr2 was increased in RC male hypothalamus, but a down-expression of most eCBs-metabolizing enzymes (Faah, Daglα, Daglβ, Mgll) and several key regulators of fatty-acid β-oxidation (Cpt1b, Acox1), mitochondrial respiration (Cox4i1), and lipid flux (Pparγ) was found in their PAT. The female offspring from calorie-restricted dams exhibited higher plasma levels of LDL and glucose as well as a reduction in chocolate and caloric intake at post-weaning periods in the feeding tests. Their liver showed a decreased gene expression of Cnr1, Pparα, Pparγ, the eCBs-degrading enzymes Faah and Mgll, the de novo lipogenic enzymes Acaca and Fasn, and the liver-specific cholesterol biosynthesis regulators Insig1 and Hmgcr. Our results suggest that the long-lasting adaptive responses to maternal caloric restriction affected cannabinoid-regulated mechanisms involved in feeding behavior, adipose β-oxidation, and hepatic lipid and cholesterol biosynthesis in a sex-dependent manner.
Highlights
Overnutrition is an important life style factor for the development of metabolic syndrome, obesity, cardiovascular disease and diabetes mellitus (Alberti et al, 2009), maternal undernutrition resulting in early life nutritional unbalance can be related to the onset of long-term metabolic alterations observed later in life
This study demonstrates that the maternal exposure to a moderate (20%) caloric restriction during preconceptional (2 weeks) and gestational periods produced long-term effects on body weight, feeding behavior and gene expression of key components of the endocannabinoid system (ECS) in a sex-dependent manner
The adult male offspring from calorie-restricted dams exhibited an increased gene expression of the cannabinoid receptors Cnr1 and Cnr2 in the hypothalamus, and showed a decreased gene expression of the eCBs-metabolizing enzymes Napepld in liver, and Faah, Daglα, Daglβ, and Mgll in perirenal adipose tissue (PAT). These results likely indicate that the up-expression of the cannabinoid receptors in the hypothalamus at adulthood may result from a lower long-term cannabinoid activity that, in turn, could be produced by lower levels of eCBs and Nacylethanolamines (NAEs) in the hypothalamus of male offspring as was previous described at birth (Ramírez-López et al, 2016)
Summary
Overnutrition is an important life style factor for the development of metabolic syndrome, obesity, cardiovascular disease and diabetes mellitus (Alberti et al, 2009), maternal undernutrition resulting in early life nutritional unbalance can be related to the onset of long-term metabolic alterations observed later in life. This process has been called nutritional programming (Lucas, 1991; Hales and Barker, 2001; Gluckman and Hanson, 2004; Barker, 2007; Vaag et al, 2012). We should not discard a predictive marker of impaired fetal nutrition in those cases with absence of low birth weight
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