Cannabidiol treatment improves metabolic profile and decreases hypothalamic inflammation caused by maternal obesity

Abstract

Introduction: The implications of maternal overnutrition on offspring metabolic and neuroimmune development are well-known. Increasing evidence now suggests that maternal obesity and poor dietary habits during pregnancy and lactation can increase the risk of central and peripheral metabolic dysregulation in the offspring, but the mechanisms are not sufficiently established. Furthermore, despite many studies addressing preventive measures targeted at the mother, very few propose practical approaches to treat the damages when they are already installed.

Methods: Here we investigated the potential of cannabidiol (CBD) treatment to attenuate the effects of maternal obesity induced by a cafeteria diet on hypothalamic inflammation and the peripheral metabolic profile of the offspring in Wistar rats.

Results: We have observed that maternal obesity induced a range of metabolic imbalances in the offspring in a sex-dependant manner, with higher deposition of visceral white adipose tissue, increased plasma fasting glucose and lipopolysaccharides (LPS) levels in both sexes, but the increase in serum cholesterol and triglycerides only occurred in females, while the increase in plasma insulin and the homeostatic model assessment index (HOMA-IR) was only observed in male offspring. We also found an overexpression of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNFα), interleukin (IL) 6, and interleukin (IL) 1β in the hypothalamus, a trademark of neuroinflammation. Interestingly, the expression of GFAP, a marker for astrogliosis, was reduced in the offspring of obese mothers, indicating an adaptive mechanism to in utero neuroinflammation. Treatment with 50 mg/kg CBD oil by oral gavage was able to reduce white adipose tissue and revert insulin resistance in males, reduce plasma triglycerides in females, and attenuate plasma LPS levels and overexpression of TNFα and IL6 in the hypothalamus of both sexes.

Discussion: Together, these results indicate an intricate interplay between peripheral and central counterparts in both the pathogenicity of maternal obesity and the therapeutic effects of CBD. In this context, the impairment of internal hypothalamic circuitry caused by neuroinflammation runs in tandem with the disruptions of important metabolic processes, which can be attenuated by CBD treatment in both ends.

Keywords: cannabidiol; hypothalamus; insulin resistance; maternal obesity; neuroinflammation.

FIGURE 1

Experimental design. CT, control chow-fed dam; CAF, cafeteria diet-fed dam; Veh, offspring treated with vehicle (corn oil); CBD, offspring treated with cannabidiol (50 mg/kg); PND, post-natal day.

FIGURE 2

Dams’ body weight throughout the experiment. Cafeteria diet-fed (CAF) dams presented significantly higher body weight when compared to control diet (CT) from the 9th week of diet, which was consistent until mating (12th week of diet) and after weaning of the offspring (19th week of diet). Data are presented as mean ± SEM. n = 9/group. *p < 0.05 **p < 0.01.

FIGURE 3

Offspring’s body weight and visceral white adipose tissue (WAT). Neither male nor female offspring showed influences of maternal diet or cannabidiol (CBD) treatment in weight at weaning (PND21) and the following 3 weeks of treatment (A). Maternal diet increased visceral fat deposit in both male and female cafeteria diet (CAF)-Veh offspring with CBD effect only in males (B). Data are presented as mean ± SEM. n = 8–10/group. *p < 0.05 ^**p < 0.01 ^***p < 0.001.

FIGURE 4

Offspring’s plasma levels of total cholesterol and triglycerides. Female cafeteria diet (CAF)-cannabidiol (CBD) presented higher levels of plasma cholesterol than control diet (CT)-CBD (A). Maternal diet increased triglyceride levels in females, but CBD treatment was able to revert this effect (B). No differences were seen in males. Data are presented as mean ± SEM. n = 8–10/group. *p < 0.05 ^***p < 0.001.

FIGURE 5

Plasma levels of glucose and insulin and calculated homeostatic model assessment (HOMA-IR) index of the offspring. Maternal obesity increased fasting glucose levels in both male and female offspring with no cannabidiol (CBD) effect (A). Maternal obesity increased levels of plasma insulin in males, but CBD treatment was able to revert this damage (B). Male cafeteria (CAF)-vehicle (Veh) presented an elevated HOMA-IR index, which was alleviated by CBD treatment (C). Data are presented as mean ± SEM. n = 8–10/group. *p < 0.05 ^***p < 0.01.

FIGURE 6

Plasma levels of lipopolysaccharides (LPS) of the offspring. Maternal obesity increased circulating LPS in both males and females, but cannabidiol (CBD) treatment was able to decrease its levels. Data are presented as mean ± SEM. n = 8–10/group. *p < 0.05 ^****p < 0.0001.

FIGURE 7

Relative gene expression of tumor necrosis factor-alpha (TNFα), interleukin 6 (IL6), interleukin 1β (IL1β), glial fibrillary acidic protein (GFAP), and ionized calcium-binding adapter molecule 1 (IBA1) in the hypothalamus of the offspring. Maternal obesity increased the expression of TNFα (A) and IL6 (B) in both males and females, with a positive effect of cannabidiol (CBD) treatment. Maternal obesity increased the expression of IL1β only in females, with no effect of CBD (C). Both maternal obesity and CBD treatment decreased GFAP expression in males and females when compared to control diet (CT) (D). No difference was found in IBA1 expression (E). Data are presented as mean ± SEM. n = 6–8/group. *p < 0.05 ^**p < 0.01 ^***p < 0.001.