Maternal Obesity Reshapes Breast Milk’s Endocannabinoid Landscape – A Missing Link in Metabolic Inheritance

A growing body of research has established that the endocannabinoid system (ECS) is dysregulated in obesity. In both human and animal studies, obesity is associated with increased concentrations of endocannabinoids, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in circulation and in metabolic tissues (Engeli, 2008; Fisk et al., 2021; Rakotoarivelo et al., 2024). This increased endocannabinoid tone is thought to stimulate cannabinoid receptors, particularly CB1, in a manner that promotes energy storage and metabolic dysfunction (Engeli, 2008; Rakotoarivelo et al., 2024). The mechanisms underlying this dysregulation are complex and may involve both increased synthesis and decreased degradation of endocannabinoids, varying by tissue and species (Engeli, 2008).

The Milk Messenger: Maternal Status Shapes Infant Exposure

Recent research has extended these findings to the earliest stages of life. A 2025 study by Pontes and colleagues followed women from late pregnancy through four months postpartum and found that maternal obesity and excessive gestational weight gain were associated with significantly higher concentrations of AEA and 2-AG in mature breast milk. These elevations were positively correlated with maternal BMI, gestational weight gain, and milk triglyceride content (Pontes et al., 2025). This suggests that maternal metabolic status can directly influence the endocannabinoid milieu to which infants are exposed during critical periods of development. Further supporting the link between maternal metabolic status and offspring development via milk, a 2024 study by Fradet and colleagues examined the milk endocannabinoidome (eCBome) in mothers with and without Gestational Diabetes Mellitus (GDM). They found distinct eCBome profiles, notably higher levels of N-palmitoylethanolamine (PEA) and certain 2-monoacylglycerols in milk from GDM mothers. Crucially, higher levels of N-acylethanolamines (NAEs, the class including AEA) in milk were negatively correlated with infant weight-for-age Z-scores at two months, specifically among infants born to GDM mothers. This provides the first direct human evidence, albeit correlational, linking altered milk endocannabinoid components, driven by maternal metabolic dysregulation, to early infant growth patterns.

However, findings from animal models introduce important nuances. Contrasting with the human obesity studies, Dias-Rocha and colleagues (2023) found that feeding rats a high-fat diet (29% fat) during gestation and lactation actually decreased the milk content of AEA and 2-AG. This reduced endocannabinoid exposure during lactation was speculated to induce adaptive changes, particularly in male offspring. These male pups exhibited increased cannabinoid and dopamine signaling in the nucleus accumbens – a key brain reward center – and subsequently showed a higher preference for fat in adolescence, despite the lower milk endocannabinoid levels (Dias-Rocha et al., 2023). These findings highlight potential species differences and underscore the complexity of how maternal diet impacts milk composition and offspring programming, suggesting that the type of diet or metabolic state may matter. Crucially, they also introduce the critical concept of sex-specific vulnerability, where male and female offspring can respond differently to the same early-life nutritional cues.

The Dual Role of the Endocannabinoid System

The ECS is a central regulator of energy homeostasis, modulating appetite, lipid metabolism, and glucose handling (Engeli, 2008; Rakotoarivelo et al., 2024; Fisk et al., 2021). Chronic activation of hypothalamic CB1 receptors, for instance, increases hunger and reduces satiety, creating a cycle that promotes overeating and impaired glucose metabolism (Engeli, 2008). At the same time, the ECS is involved in neurodevelopment, influencing synaptic pruning and neurotransmitter systems, including dopamine, that are relevant for both metabolic regulation and social behavior (Sakayori et al., 2020; Dias-Rocha et al., 2023).

The Omega Imbalance: Driving ECS Dysregulation

Dietary patterns play a crucial role in shaping ECS activity. The modern Western diet is characterized by a high omega-6 to omega-3 fatty acid ratio-often exceeding 20:1, compared to an ancestral ratio closer to 1:1 (Simopoulos, 2002). Omega-6 fatty acids are metabolized to arachidonic acid, the direct precursor for AEA and 2-AG. Thus, excessive omega-6 intake increases the substrate pool for endocannabinoid synthesis. Animal studies confirm that increasing dietary linoleic acid (an omega-6 fatty acid) elevates tissue levels of AEA and 2-AG, particularly in the liver (Alvheim et al., 2012).

Developmental Programming: Metabolism, Behavior, and Sex Differences

The developmental consequences of this nutritional programming can be profound and long-lasting, often exhibiting sex differences. In mice, maternal diets with a high omega-6 to omega-3 ratio induce overeating and hedonic food preferences in offspring, mediated by upregulation of the midbrain dopaminergic system (Sakayori et al., 2020). Similarly, the previously mentioned rat study showed males developing a fat preference after exposure to milk with lower eCBs from high-fat fed dams (Dias-Rocha et al., 2023). Furthermore, perinatal exposure to a maternal high-fat diet in rats can lead to persistent ECS alterations in the liver of adult offspring, including increased cannabinoid receptor expression and changes in metabolizing enzymes. These changes are associated with increased liver triglyceride content (steatosis) and oxidative stress, with male offspring often showing greater susceptibility to these liver abnormalities compared to females (Miranda et al., 2018).

In humans, the data from Pontes et al. (2025) and Fradet et al. (2024) demonstrate that maternal metabolic conditions result in altered endocannabinoid exposure for infants via breast milk, with potential consequences for growth and development. While the Pontes study highlights the potential influence on appetite and metabolic set points, and the Fradet study provides a direct correlation with infant weight metrics, the contrasting animal data (Dias-Rocha et al., 2023) remind us of the complexities involved, including potential species differences and crucial sex-specific responses.

Exploring the ECS-Autism Spectrum Connection

There is also emerging evidence linking ECS dysregulation to neurodevelopmental conditions such as autism spectrum disorder (ASD). Children with ASD have been shown to exhibit reduced endocannabinoid signaling, including lower levels of AEA and 2-AG, and altered expression of cannabinoid receptors (Wen et al., 2021). In animal models, boosting 2-AG levels ameliorates ASD-like behaviors (Wen et al., 2021). While direct evidence in humans linking maternal ECS activity, breast milk endocannabinoids, and ASD risk is lacking, these findings highlight a plausible shared pathway potentially influenced by early-life nutritional programming, which may also interact with sex-specific vulnerabilities.

Breaking the Cycle: Potential Solutions Through Nutrition

Interventions that target maternal nutrition may offer a way to modulate ECS activity and improve offspring outcomes. Omega-3 supplementation, for example, can normalize endocannabinoid levels in adipose tissue and may counteract the pro-inflammatory and obesogenic effects of excessive omega-6 intake (Fisk et al., 2021). The Fisk et al. study utilized a dose of 3g/day (EPA+DHA); notably, meta-analyses suggest doses in the 2-3 g/day range are optimal for cardiovascular benefits like blood pressure reduction, implying this dose is metabolically significant (Zhang et al., 2023).

Beyond systemic effects, the benefits of omega-3 may extend directly to brain ECS function relevant for neurodevelopment. A 2024 study in mice demonstrated that an omega-3 rich diet significantly modulated the hippocampal ECS, increasing levels of CB1 receptors (~30%) and MAGL (the enzyme degrading 2-AG), while decreasing DAGLα (an enzyme synthesizing 2-AG) (Serrano et al., 2024). These molecular changes were associated with enhanced synaptic plasticity dependent on 2-AG/CB1 signaling, improved object recognition memory, and reduced anxiety-like behavior (Serrano et al., 2024). These findings suggest omega-3 fatty acids don’t just passively alter precursor balance but actively enhance specific ECS signaling pathways in the brain crucial for learning, memory, and emotional regulation, providing a stronger mechanistic basis for their potential role in mitigating neurodevelopmental risks. Adjusting the dietary omega-6/omega-3 ratio-by increasing intake of omega-3-rich foods and reducing consumption of seed oils and grain-fed animal products-can reduce the precursor pool for endocannabinoid synthesis and potentially restore ECS balance (Simopoulos, 2002; Alvheim et al., 2012).

Conclusion: A Call for Action on Maternal Nutrition

In summary, the ECS acts as a critical interface between maternal metabolic health, early-life nutrition, and the developmental programming of metabolic, hepatic, and neurobehavioral traits. The findings from Pontes et al. (2025) and Fradet et al. (2024) in humans, contrasted with animal studies like Dias-Rocha et al. (2023) and Miranda et al. (2018), underscore the importance of maternal nutrition and metabolic status in shaping offspring health trajectories, while also highlighting complexities such as potential species differences and significant sex-specific vulnerabilities. While further research is needed to clarify the causal pathways and long-term outcomes in humans, optimizing maternal diet-particularly the balance of omega-6 and omega-3 fatty acids, potentially supported by supplementation at effective doses-offers a promising strategy. However, realizing this potential demands a fundamental shift: recognizing omega-3 fatty acids as essential nutrients for pregnancy, deserving of consideration similar to folic acid. Given their established role in preventing preterm birth and supporting fetal neurodevelopment, coupled with evidence of inadequate intake in many women (often unmet even by standard prenatal supplements), prioritizing sufficient omega-3 status through diet and targeted supplementation must become a standard of care to truly break the cycle of metabolic and potentially neurodevelopmental disorders across generations.

References:

1. Alvheim AR, Malde MK, Osei-Hyiaman D, et al. Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity. Obesity (Silver Spring). 2012;20(10):1984-1994.
2. Dias-Rocha CP, Costa JCB, Oliveira YS, et al. Maternal high-fat diet decreases milk endocannabinoids with sex-specific changes in the cannabinoid and dopamine signaling and food preference in rat offspring. Front Endocrinol (Lausanne). 2023;14:1087999.
3. Engeli S. Dysregulation of the endocannabinoid system in obesity. J Neuroendocrinol. 2008;20 Suppl 1:110-115.
4. Fisk HL, Childs CE, Miles EA, et al. Dysregulation of endocannabinoid concentrations in human subcutaneous adipose tissue in obesity and modulation by omega-3 polyunsaturated fatty acids. Clin Sci (Lond). 2021;135(1):185-200.
5. Fradet A, Castonguay-Paradis S, Dugas C, et al. The human milk endocannabinoidome and neonatal growth in gestational diabetes. Front Endocrinol (Lausanne). 2024;15:1415630.
6. Katakura M, Hamazaki K, et al. Maternal dietary imbalance between omega-6 and omega-3 fatty acids triggers the offspring’s overeating in mice. Commun Biol. 2020;3:473.
7. Miranda RA, De Almeida MM, Rocha CPDD, et al. Maternal high-fat diet consumption induces sex-dependent alterations of the endocannabinoid system and redox homeostasis in liver of adult rat offspring. Sci Rep. 2018;8(1):14751.
8. Pontes TF, Reis G, Santos GRC, et al. Maternal Obesity and Excessive Gestational Weight Gain Influence Endocannabinoid Levels in Human Milk Across Breastfeeding: Potential Implications for Offspring Development. Nutrients. 2025;17(8):1344.
9. Rakotoarivelo V, Allam-Ndoul B, Martin C, et al. Investigating the alterations of endocannabinoidome signaling in the human small intestine in the context of obesity and type 2 diabetes. Heliyon. 2024;10(6):e26968.
10. Sakayori N, Katakura M, Hamazaki K, et al. Maternal dietary imbalance between omega-6 and omega-3 fatty acids triggers the offspring’s overeating in mice. Commun Biol. 2020;3(1):473.
11. Serrano M, Saumell-Esnaola M, Ocerin G, et al. Impact of Omega-3 on Endocannabinoid System Expression and Function, Enhancing Cognition and Behavior in Male Mice. Nutrients. 2024;16(24):4344.
12. Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother. 2002;56(8):365-379.
13. Wen TH, et al. Alterations of the endocannabinoid system and its therapeutic potential in autism spectrum disorder. Open Biol. 2021;11(2):200306.
14. Zhang X, Ritonja JA, Zhou N, Chen BE, Li X. Omega-3 Polyunsaturated Fatty Acids Intake and Blood Pressure: A Dose-Response Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc. 2022;11(11):e025071.