Changes in mu-opioid receptor expression and function in the mesolimbic system after long-term access to a palatable diet

Pitman, Kimberley A; Borgland, Stephanie L.

doi:10.1016/j.pharmthera.2015.07.005

Cited by 16 publications

(10 citation statements)

References 131 publications

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“…Indeed, Oprm1 agonist morphine injected into the PAG decrease fear and promotes analgesia, while morphine withdrawal is associated with anxiogenesis (De Ross et al, 2009; Halladay and Blair, 2012; Twardowschy and Coimbra, 2015). In humans, obesity is associated with decreased Oprm1 availability in the brain, which would support the notion that obesity raises fear levels (Karlsson et al, 2015; Pitman and Borgland, 2015). …”

Section: Discussionsupporting

confidence: 63%

How Metabolic State May Regulate Fear: Presence of Metabolic Receptors in the Fear Circuitry

et al. 2018

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Metabolic status impacts on the emotional brain to induce behavior that maintains energy balance. While hunger suppresses the fear circuitry to promote explorative food-seeking behavior, satiety or obesity may increase fear to prevent unnecessary risk-taking. Here we aimed to unravel which metabolic factors, that transfer information about the acute and the chronic metabolic status, are of primary importance to regulate fear, and to identify their sites of action within fear-related brain regions. We performed a de novo analysis of central and peripheral metabolic factors that can penetrate the blood–brain barrier using genome-wide expression data across the mouse brain from the Allen Brain Atlas (ABA). The central fear circuitry, as defined by subnuclei of the amygdala, the afferent hippocampus, the medial prefrontal cortex and the efferent periaqueductal gray, was enriched with metabolic receptors. Some of their corresponding ligands were known to modulate fear (e.g., estrogen and thyroid hormones) while others had not been associated with fear before (e.g., glucagon, ACTH). Additionally, several of these enriched metabolic receptors were coexpressed with well-described fear-modulating genes (Crh, Crhr1, or Crhr2). Co-expression analysis of monoamine markers and metabolic receptors suggested that monoaminergic nuclei have differential sensitivity to metabolic alterations. Serotonergic neurons expressed a large number of metabolic receptors (e.g., estrogen receptors, fatty acid receptors), suggesting a wide responsivity to metabolic changes. The noradrenergic system seemed to be specifically sensitive to hypocretin/orexin modulation. Taken together, we identified a number of novel metabolic factors (glucagon, ACTH) that have the potential to modulate the fear response. We additionally propose novel cerebral targets for metabolic factors (e.g., thyroid hormones) that modulate fear, but of which the sites of action are (largely) unknown.

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Section: Discussionsupporting

confidence: 63%

How Metabolic State May Regulate Fear: Presence of Metabolic Receptors in the Fear Circuitry

et al. 2018

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“…Although we cannot rule out the possibility that LCS exposure also reduced energy expenditure in our rats, analysis of white adipose tissue revealed no differences in genes related to energy expenditure in our study. Mu-opioid receptor upregulation has been linked to greater intake of palatable food, specifically food that is high in fat and may occur as a result of heightened responsiveness to endogenous and exogenous opioids in this region 52. In our LCS offspring, altered mesolimbic gene expression did not translate into greater food intake and may not have directly contributed to the observed metabolic phenotype.…”

Section: Discussionmentioning

confidence: 66%

Maternal low-dose aspartame and stevia consumption with an obesogenic diet alters metabolism, gut microbiota and mesolimbic reward system in rat dams and their offspring

Nettleton

Cho

Klančič

et al. 2020

Gut

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ObjectiveWe examined the impact of maternal low-dose aspartame and stevia consumption on adiposity, glucose tolerance, gut microbiota and mesolimbic pathway in obese dams and their offspring.DesignFollowing obesity induction, female Sprague-Dawley rats were allocated during pregnancy and lactation to: (1) high fat/sucrose diet (HFS) +water (obese-WTR); (2) HFS +aspartame (obese-APM; 5–7 mg/kg/day); (3) HFS +stevia (obese-STV; 2–3 mg/kg/day). Offspring were weaned onto control diet and water and followed until 18 weeks. Gut microbiota and metabolic outcomes were measured in dams and offspring. Cecal matter from offspring at weaning was used for faecal microbiota transplant (FMT) into germ-free (GF) mice.ResultsMaternal APM and STV intake with a HFS diet increased body fat in offspring at weaning and body weight long-term with APM. Maternal APM/HFS consumption impaired glucose tolerance in male offspring at age 8 weeks and both APM and STV altered faecal microbiota in dams and offspring. Maternal obesity/HFS diet affected offspring adiposity and glucose tolerance more so than maternal LCS consumption at age 12 and 18 weeks. APM and STV altered expression of genes in the mesolimbic reward system that may promote consumption of a palatable diet. GF mice receiving an FMT from obese-APM and obese-STV offspring had greater weight gain and body fat and impaired glucose tolerance compared with obese-WTR.ConclusionMaternal low-calorie sweetener consumption alongside HFS may disrupt weight regulation, glucose control and gut microbiota in dams and their offspring most notably in early life despite no direct low-calorie sweetener consumption by offspring.

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“…[124][125][126] Consistent with these findings, early evidence linked obesity to decreased D2 receptor availability. [127][128][129] Wang et al 27 explored the striatum using PET scans for [ 11 C]raclopride. Later, it was reported that individuals with severe obesity (average BMI of 51.5) also exhibited lower D2R binding in PFC regions.…”

Section: Dopaminergic Changes In Obesity and Following Hfdmentioning

confidence: 99%

“…Consumption of high‐fat food activates the mesolimbic dopaminergic system, the same circuit that is activated by drugs of abuse . Animals exposed to palatable foods can also become resistant to outcome devaluation, suggesting that palatable foods can facilitate habitual behaviors . Here, we seek to outline a framework of circuit‐based changes in substance use disorders and discuss how similar circuit adaptations may underlie the persistent behavioral changes seen in obesity.…”

Section: Common Circuits Behaviors and Underlying Mechanisms Betweementioning

confidence: 99%

Persistent effects of obesity: a neuroplasticity hypothesis

Matikainen‐Ankney

Kravitz

2018

Annals of the New York Academy of Sciences

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The obesity epidemic is a leading cause of health problems in the United States, increasing the risk of cardiovascular, endocrine, and psychiatric diseases. Although many people lose weight through changes in diet and lifestyle, keeping the weight off remains a challenge. Here, we discuss a hypothesis that seeks to explain why obesity is so persistent. There is a great degree of overlap in the circuits implicated in substance use disorder and obesity, and neural plasticity of these circuits in response to drugs of abuse is well documented. We hypothesize that obesity is also associated with neural plasticity in these circuits, and this may underlie persistent changes in behavior, energy balance, and body weight. Here, we discuss how obesity-associated reductions in motivation and physical activity may be rooted in neurophysiological alterations in these circuits. Such plasticity may alter how humans and animals use, expend, and store energy, even after weight loss.

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Changes in mu-opioid receptor expression and function in the mesolimbic system after long-term access to a palatable diet

Cited by 16 publications

References 131 publications

How Metabolic State May Regulate Fear: Presence of Metabolic Receptors in the Fear Circuitry

How Metabolic State May Regulate Fear: Presence of Metabolic Receptors in the Fear Circuitry

Maternal low-dose aspartame and stevia consumption with an obesogenic diet alters metabolism, gut microbiota and mesolimbic reward system in rat dams and their offspring

Persistent effects of obesity: a neuroplasticity hypothesis

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