Maternal high-dense diet programs interferon type I signaling and microglia complexity in the nucleus accumbens shell of rats showing food addiction-like behavior.

OBJECTIVE: This study aimed to characterize the molecular immune networks and microglia reactivity in the nucleus accumbens (NAc) shell affected by fetal nutritional programming leading to addiction-like behavior in the offspring of Wistar rats. Fetal nutritional programming by energy-dense foods leads to addiction-like behavior in the offspring. Exposure to energy-dense foods also activates systemic and central inflammation in the offspring. METHODS: Females Wistar rats were exposed to cafeteria (CAF) diet or control diet for 9 weeks (prepregnancy, pregnancy and lactation), and male offspring at 2 months of age were diagnosed with food addiction-like behavior using operant conditioning. Global microarray analysis, RTqPCR, proinflammatory plasma profile and microglia immunostaining were performed in the NAc shell of male rats. SIM-A9 microglia cells were stimulated with IFN-α and palmitic acid, and microglia activation and phagocytosis were determined by RTqPCR and incubation of green-fluorescent latex beads, respectively. RESULTS: Microarray analysis in the NAc shell of the male offspring exposed to CAF during development and diagnosed with addiction-like behavior showed increasing in the type I interferon-inducible gene, Ift1 , gene network. Genomic and cellular characterization also confirmed microglia hyperreactivity and upregulation of the Ifit1 in the NAc shell of animals with addiction-like behavior. In-vitro models demonstrated that microglia do respond to IFN-α promoting a time-dependent genomic expression of Ift1, IL-1ß and IL-6 followed by increased phagocytosis. CONCLUSION: Prenatal exposure to energy-dense foods primes the IFN type I signaling and microglia complexity in the NAc shell of rats diagnosed with food addiction-like behavior.

Converging vulnerability factors for compulsive food and drug use.

Highly palatable foods and substance of abuse have intersecting neurobiological, metabolic and behavioral effects relevant for understanding vulnerability to conditions related to food (e.g., obesity, binge eating disorder) and drug (e.g., substance use disorder) misuse. Here, we review data from animal models, clinical populations and epidemiological evidence in behavioral, genetic, pathophysiologic and therapeutic domains. Results suggest that consumption of highly palatable food and drugs of abuse both impact and conversely are regulated by metabolic hormones and metabolic status. Palatable foods high in fat and/or sugar can elicit adaptation in brain reward and withdrawal circuitry akin to substances of abuse. Intake of or withdrawal from palatable food can impact behavioral sensitivity to drugs of abuse and vice versa. A robust literature suggests common substrates and roles for negative reinforcement, negative affect, negative urgency, and impulse control deficits, with both highly palatable foods and substances of abuse. Candidate genetic risk loci shared by obesity and alcohol use disorders have been identified in molecules classically associated with both metabolic and motivational functions. Finally, certain drugs may have overlapping therapeutic potential to treat obesity, diabetes, binge-related eating disorders and substance use disorders. Taken together, data are consistent with the hypotheses that compulsive food and substance use share overlapping, interacting substrates at neurobiological and metabolic levels and that motivated behavior associated with feeding or substance use might constitute vulnerability factors for one another. This article is part of the special issue on 'Vulnerabilities to Substance Abuse'.

Food Addiction and Psychosocial Adversity: Biological Embedding, Contextual Factors, and Public Health Implications.

The role of stress, trauma, and adversity particularly early in life has been identified as a contributing factor in both drug and food addictions. While links between traumatic stress and substance use disorders are well documented, the pathways to food addiction and obesity are less established. This review focuses on psychosocial and neurobiological factors that may increase risk for addiction-like behaviors and ultimately increase BMI over the lifespan. Early childhood and adolescent adversity can induce long-lasting alterations in the glucocorticoid and dopamine systems that lead to increased addiction vulnerability later in life. Allostatic load, the hypothalamic-pituitary-adrenal axis, and emerging data on epigenetics in the context of biological embedding are highlighted. A conceptual model for food addiction is proposed, which integrates data on the biological embedding of adversity as well as upstream psychological, social, and environmental factors. Dietary restraint as a feature of disordered eating is discussed as an important contextual factor related to food addiction. Discussion of various public health and policy considerations are based on the concept that improved knowledge of biopsychosocial mechanisms contributing to food addiction may decrease stigma associated with obesity and disordered eating behavior.

Low carbohydrate ketogenic therapy as a metabolic treatment for binge eating and ultraprocessed food addiction.

PURPOSE OF REVIEW: The aim of this study was to highlight the recent advancements and future directions for potential use of a low carbohydrate ketogenic dietary approach to treat binge eating and ultraprocessed food addiction. Herein, we explore proposed mechanisms of why a diet low in refined carbohydrates, processed sugar and higher fat content may be helpful in alleviating symptoms. RECENT FINDINGS: Emerging evidence suggests there may be a metabolic role in development of maladaptive eating. These findings broaden our understanding of eating psychopathology causes. Ultraprocessed, refined or high glycemic index carbohydrates are a possible trigger mediating neurochemical responses similar to addiction. The carbohydrate-insulin model of obesity supports observations of these foods triggering abnormal blood sugar and insulin spikes subsequently leading to changes in metabolic and neurobiological signaling. This results in overeating symptoms and hunger exacerbation, which differs from observed effects of healthy fat consumption and lack of similar insulin spikes. As supported in recent case series, significantly reducing or abstaining from these addictive-like ultraprocessed foods and highly refined carbohydrates could be considered a treatment approach. SUMMARY: The current review highlights recent and pertinent evidence with respect to theoretical and practical application of low carbohydrate ketogenic therapeutic approaches for ultraprocessed food addiction and binge eating symptoms. VIDEO ABSTRACT:.

Associations of food addiction with metabolic control, medical complications and depression among patients with type 2 diabetes.

AIMS: Food addiction (FA) is conceptualized as a behavioral pattern that is similar in some ways to addictions to alcohol and other substances. This disorder has not been well studied among patients with type 2 diabetes (T2DM). We aimed to analyze if there is any relationship between FA and clinical or psychological variables among patients with T2DM. METHODS: Three hundred patients with T2DM were analyzed cross-sectionally. Participants were evaluated for the presence of FA by completing the Yale Food Addiction Scale 2.0 questionnaire. RESULTS: 29.3% of patients screened positive for FA. Patients with FA had a greater BMI (33.41 ± 7.5 vs. 31.6 ± 5.9 kg/m2; p = 0.04). HbA1c was higher among individuals with FA (7.9 ± 4.4 vs. 7.6 ± 1.4%, p = 0.008). The proportion of subjects with diabetic retinopathy, neuropathy and nephropathy was greater among patients with criteria for FA compared with patients without this condition (25% vs. 13.2%, 29.5% vs. 21.8% and 32% vs. 22.3%; p = 0.03, p = 0.05 and p = 0.05, respectively). The percentage of patients with FA with significant depressive symptoms was also greater (36.4% vs. 18.5%; p = 0.002). CONCLUSIONS: The presence of FA among T2DM patients implied a worse glycaemic control. Microvascular complications and depressive symptoms were higher among these patients.

Towards a comprehensive theory of obesity and a healthy diet: The causal role of oxidative stress in food addiction and obesity.

BACKGROUND: Obesity is a major public health problem whose prevalence has been rapidly increasing in the United States (U.S), and globally. It is one of the leading causes of preventable deaths globally and contributes to the development of many diseases. METHODS: The search was limited to studies published in English and other languages involving both animal and human subjects. Articles selected included preclinical studies, randomized clinical trials RCTs, observational studies, meta-analyses, narrative and systemic reviews providing primary quantitative data with a measure of obesity or food addiction as an outcome. Over 5000 articles were found in the first round of search which was filtered to 506 articles. RESULTS: Oxidative stress plays a critical role in food addiction and is both a cause and mediator of obesity. Reactive oxygen species play a direct role in adipogenesis and oxidative stress modulates all factors involved in obesity including genetics, sleep, gut microbiome, insulin, ghrelin, inflammation, adipokines, leptin, stress, HPA axis, and the hypothalamus. CONCLUSIONS: The idea of thinking of combating obesity from the lens of calorie count, low carbohydrate, high or low-fat, vegetarian, vegan, plant-based, or animal-based diet is fundamentally wrong. The best way to look at obesity is through the framework of systemic redox homeostasis. Since redox homeostasis is tilted towards increased reactive oxygen species production, and excessive antioxidant intake can result in oxidative stress, an antioxidant and prooxidant food ratio of 2:3 per meal is the ideal nutritional ratio for good health and ideal weight. A ratio of 3:4 is ideal for obese individuals because of their state of chronic oxidative stress and inflammation. Physical activity, sleep quality, psychological stress, maternal prenatal diet and oxidative stress promoting disease conditions are important modulators of oxidative stress and obesity.

Reward sensitivity deficits in a rat model of compulsive eating behavior.

Compulsive eating behavior is hypothesized to be driven in part by reward deficits likely due to neuroadaptations to the mesolimbic dopamine (DA) system. Therefore, the aim of this study was to assess deficits in reward system functioning and mesolimbic DA after alternating a standard chow with palatable diet, a model of compulsive eating. In this model, rats in the control group (Chow/Chow) are provided a standard chow diet 7 days a week, while the experimental group (Chow/Palatable) is provided chow for 5 days a week ("C Phase"), followed by 2 days of access to a highly palatable sucrose diet ("P Phase"). We first tested the sensitivity to d-Amphetamine's stimulatory, reward-enhancing, and primary rewarding effects using a locomotor activity assay, an intracranial self-stimulation (ICSS) procedure, and a conditioned place preference test, respectively. We then quantified DA release in the nucleus accumbens (NAc) shell after treatment with d-Amphetamine using in vivo microdialysis, quantified levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA using quantitative polymerase chain reaction (qPCR), and lastly, quantified baseline extracellular DA and function of DAT in vivo using quantitative "no-net-flux" microdialysis. Chow/Palatable rats displayed blunted d-Amphetamine-induced locomotor activity, insensitivity to d-Amphetamine potentiation of ICSS threshold, and decreased place preference for d-Amphetamine during the P Phase. We found that Chow/Palatable rats had blunted DA efflux following d-Amphetamine treatment. Furthermore, DAT mRNA was increased in Chow/Palatable rats during the P Phase. Finally, quantitative "no-net-flux" microdialysis revealed reduced extracellular baseline DA and DAT function in Chow/Palatable rats. Altogether, these results provide evidence of reduced reward system functioning and related neuroadaptations in the DA and DAT systems in this model of compulsive eating. Reward deficits, resulting from repeated overeating, may in turn contribute to the perpetuation of compulsive eating behavior.

Nucleus accumbens inflammation mediates anxiodepressive behavior and compulsive sucrose seeking elicited by saturated dietary fat.

OBJECTIVE: The incidence of depression is significantly compounded by obesity. Obesity arising from excessive intake of high-fat food provokes anxiodepressive behavior and elicits molecular adaptations in the nucleus accumbens (NAc), a region well-implicated in the hedonic deficits associated with depression and in the control of food-motivated behavior. To determine the etiology of diet-induced depression, we studied the impact of different dietary lipids on anxiodepressive behavior and metabolic and immune outcomes and the contribution of NAc immune activity. METHODS: Adult C57Bl/6 mice were subjected to isocaloric high-fat/high-sucrose diets (HFD), enriched in either saturated or monounsaturated fat, or a control low-fat diet (LFD). Metabolic responses, anxiodepressive behavior, and plasma and NAc inflammatory markers were assessed after 12 weeks. In separate experiments, an adenoviral construct inhibiting IKKß, an upstream component of the nuclear factor kappa-b (NFkB) pathway, was a priori injected into the NAc. RESULTS: Both HFDs resulted in obesity and hyperleptinemia; however, the saturated HFD uniquely triggered anxiety-like behavior, behavioral despair, hyperinsulinemia, glucose intolerance, peripheral inflammation, and multiple pro-inflammatory signs in the NAc, including reactive gliosis, increased expression of cytokines, antigen-presenting markers and NFкB transcriptional activity. Selective NAc IKKß inhibition reversed the upregulated expression of inflammatory markers, prevented anxiodepressive behavior and blunted compulsive sucrose-seeking in mice fed the saturated HFD. CONCLUSIONS: Metabolic inflammation and NFкB-mediated neuroinflammatory responses in the NAc contribute to the expression of anxiodepressive behavior and heightened food cravings caused by a diet high in saturated fat and sugar.

Food Addiction and Binge Eating: Lessons Learned from Animal Models.

The feeding process is required for basic life, influenced by environment cues and tightly regulated according to demands of the internal milieu by regulatory brain circuits. Although eating behaviour cannot be considered "addictive" under normal circumstances, people can become "addicted" to this behaviour, similarly to how some people are addicted to drugs. The symptoms, cravings and causes of "eating addiction" are remarkably similar to those experienced by drug addicts, and both drug-seeking behaviour as eating addiction share the same neural pathways. However, while the drug addiction process has been highly characterised, eating addiction is a nascent field. In fact, there is still a great controversy over the concept of "food addiction". This review aims to summarize the most relevant animal models of "eating addictive behaviour", emphasising binge eating disorder, that could help us to understand the neurobiological mechanisms hidden under this behaviour, and to improve the psychotherapy and pharmacological treatment in patients suffering from these pathologies.

Similarities and Differences in Neurobiology.

Substance addiction is a chronic, relapsing brain disease characterized by compulsive drug seeking and use despite harmful consequences. Non-substance addiction is defined recently that people may compulsively engage in an activity despite any negative consequences to their lives. Despite differences with respect to their addictive object, substance addiction and non-substance addiction may share similarities with respect to biological, epidemiological, clinical, genetic and other features. Here we review the similarities and differences in neurobiology between these two addictions with a focus on dopamine, serotonin, opioid, glutamate and norepinephrine systems. Studies suggest the involvement of all these systems in both substance addiction and non-substance addiction while differences may exist with respect to their contributions.

Dynorphin/Kappa Opioid Receptor Signaling in Preclinical Models of Alcohol, Drug, and Food Addiction.

The dynorphin/kappa opioid receptor (KOR) system is implicated in the "dark side" of addiction, in which stress exacerbates maladaptive responses to drug and alcohol exposure. For example, acute stress and acute ethanol exposure result in an elevation in dynorphin, the KOR endogenous ligand. Activation of KORs results in modulation of several neurotransmitters; however, this chapter will focus on its regulatory effects on dopamine in mesolimbic areas. Specifically, KOR activation has an inhibitory effect on dopamine release, thereby influencing reward processing. Repeated stimulation of KORs, for example, via chronic drug and/or stress exposure, results in increased function of the dynorphin/KOR system. This augmentation in KOR function shifts the homeostatic balance in favor of an overall reduction in dopamine signaling via either by reducing dopamine release or by increasing dopamine transporter function. This chapter examines the effects of chronic ethanol exposure on KOR function and the downstream effects on dopamine transmission. Additionally, the impact of chronic cocaine exposure and its effects on KOR function will be explored. Further, KORs may also be involved in driving excessive consumption of food, contributing to the risk of developing obesity. While some studies have shown that KOR agonists reduce drug intake, other studies have shown that antagonists reduce addiction-like behaviors, demonstrating therapeutic potential. For example, KOR inhibition reduces ethanol intake in dependent animals, motivation to self-administer cocaine in chronic stress-exposed animals, and food consumption in obese animals. This chapter will delve into the mechanisms by which modulation of the dynorphin/KOR system may be therapeutic.