Review
Is obesity a brain disease?

https://doi.org/10.1016/j.neubiorev.2013.07.015Get rights and content

Highlights

  • Excessive nutrition elicits early hypothalamic, hippocampal and cortical inflammation.

  • Hypothalamic-inflammation disrupts energy-balance, insulin secretion and sensitivity.

  • Brain insulin resistance and regional (e.g., hippocampal) atrophy evolve.

  • Brain dysfunction translates into aberrant control of eating and cognitive decline.

  • Brain disease is inseparable from obesity itself.

Abstract

That the brain is involved in the pathogenesis and perpetuation of obesity is broadly self-intuitive, but traditional evaluation of this relationship has focused on psychological and environment-dependent issues, often referred to as the “it's all in the head” axiom. Here we review evidence that excessive nutrition or caloric flux, regardless of its primary trigger, elicits a biological trap which imprints aberrant energy control circuits that tend to worsen with the accumulation of body fat. Structural and functional changes in the brain can be recognized, such as hypothalamic inflammation and gliosis, reduction in brain volume, reduced regional blood flow or diminished hippocampal size. Such induced changes collectively translate into a vicious cycle of deranged metabolic control and cognitive deficits, some of which can be traced back even to childhood or adolescence. Much like other components of the obese state, brain disease is inseparable from obesity itself and requires better recognition to allow future therapeutic targeting.

Introduction

Overeating and sedentary behavior are typically viewed as reflective of cultural, psychological or otherwise acquired addictive traits, abetted by seemingly controllable external cues, the availability of calorie-rich food and the growing ease of life, which now allows lessening linkage between voluntary movement and survival. As such, these behavioral patterns are often the target of moral judgment, which eventually contributes to physician–patient mistrust, in the treatment of obesity and its sequels, when facing the failure of the “eat less, exercise more” approach. Here we will assess existing evidence that obesity indeed is a disease of the brain. Whether brain disease in obesity is the primary event or at least a partly reversible sequel of obesity may matter less than expected from traditional rigid “cause and effect” analysis.

Section snippets

Overnutrition is a biological trap, not simply a willful choice

Animal studies may offer good insights into biologically entrenched choices of diet, as they are uncomplicated by cultural and social habituation or the complexity of human cognition. Earlier beliefs that animals can select food with precision sufficient to allow just normal growth and survival have been challenged more than two decades ago (Galef, 1991). Even if such biological precision is accepted, recent data suggest that early exposure of rats to fatty foods during the growth period

Early life overnutrition and exposure to maternal obesity reprograms eating control in adult life

Brain structural maturation is not completed in-utero but extends into the first phases of life. Hence, exposure to excessive nutrition during this critically vulnerable pre- and postnatal development periods can impair the brain in general and disrupt the finely tuned normal brain-governed feeding behavior. Such responses to over-nutrition are probably mediated through the induction of structural and functional alterations which can lead to obesity, dysmetabolism and/or cognitive disadvantage

Overnutrition elicits brain disease: relation to obesity

Cafeteria diet reportedly disrupts the blood brain barrier in the hippocampus in rats through down regulation of mRNA expression of tight junction proteins, particularly Claudin-5 and -12, in the choroid plexus (Kanoski et al., 2010), thus exposing the brain tissue to potentially damaging circulating factors which cannot normally interact with brain cells. Chronic high fat intake can lead to inflammatory changes in the brain cortex as evidenced by the presence of increased nicotinamide adenine

What is the actual culprit: high caloric intake, increased dietary fat, excessive carbohydrate consumption or the presence of obesity per se?

Identification of the critical instigator(s) of brain anomalies in the obese state is highly desirable, but unfortunately not necessarily practical. Presently, this cannot be viewed as a simple “Chicken and Egg” question, but is most likely a highly complex series of impairments, encompassing inherited defects predisposing to obesity (e.g., leptin deficiency as an extreme example), the stress imposed on the brain by increased overall caloric load, selective deleterious brain effects of fat-rich

Structural changes

Multiple structural alterations have been reported in the brain of obese subjects, some of which may be difficult to conclusively discern from the effects of aging or the concomitant presence of hypertension, atherosclerosis, dyslipidemia or abnormal glucose metabolism. Still, cross-sectional regression studies associate increased body mass index (BMI) with decreased brain volume (Ward et al., 2005) and obese humans were found to have decreased brain volumes independent of age or disease (

Differing functional brain MRI (fMRI) responses between obese and lean individuals

Imaging studies conducted in the postprandial state (i.e., after a meal) argue that the excess energy intake in obesity is at least partly due to eating in the absence of hunger (nonhomeostatic eating) presenting evidence that overweight/obese participants have greater brain activity in response to the presence of food (cues or taste) and enhancement of anticipated reward compared with normal-weight participants. For example, in the fasted state preceding a breakfast that provided 20% of

Overnutrition, hypothalamic inflammation and hypothalamic dysfunction

Proinflammatory cytokines, such as TNF-α and interleukin-1 beta (IL-1β) were shown to be released in the hypothalamus and activate apoptotic signaling in the hypothalamus of rodents placed on a high fat diet (De Souza et al., 2005). This process may be particularly prominent in the mediobasal hypothalamus. Short-term high-fat intake interferes with insulin signaling in the hypothalamus as measured by the inability of insulin delivered to the mediobasal hypothalamus to inhibit lipolysis through

Hypothalamic inflammation affects insulin release and action

Recent evidence indicates that hypothalamic inflammation results not only in impaired central regulation of energy balance but also in disruption of normal insulin secretion and reduced peripheral insulin sensitivity. ICV injection of a low dose of TNF-α leads to a dysfunctional increase in insulin secretion and activates the expression of a number of markers of apoptosis in pancreatic islets. Experimentally induced hypothalamic inflammation induced by the ICV injection of stearic acid produced

Hippocampal inflammation and atrophy

The hippocampus is a vital structure for cognition, processing of short to long term memory, learning, spatial navigation and emotions, whose function may be preserved through continued neurogenesis in adult life. As recently reviewed by Fotuhi et al. (2012), obesity and obesity-related conditions such as diabetes, hypertension, cardiovascular disease, obstructive sleep apnea, vitamin B12 deficiency, atrial fibrillation, mood disorders are known to adversely influence hippocampal size (Fotuhi

Obesity and cognitive decline

Experimental evidence links very HFD-induced obesity to cognitive decline. For example, in one study, very HFD but not moderate fat diet elicited impaired cognition, increased brain inflammation, and decreased brain-derived neurotrophic factor (BDNF), along with increased body weight. Hence some, but not all, diet formulations which increase body weight can induce brain inflammation and disrupt cognition in mice (Pistell et al., 2010). While this appears to suggest that some types of excessive

Hormonal alterations and cognitive function in obesity

Leptin replacement was shown to improve cognitive function in a boy with leptin deficiency, but the interpretation of this effect is complex, since the effects of the induced weight loss are difficult to discern from the effect of leptin per se (Paz-Filho et al., 2008). There is growing interest in the possibility that leptin and leptin analogs have neuroprotective effects (Frolich et al., 2011) and in this respect, the brain leptin resistance seen in obesity might adversely affect naturally

Sleep deprivation

Sleep deprivation and circadian disruption in the urban, western style, “24/7 Society” have been long suspected as facilitators of the spread of obesity and the MetS. On functional MRI studies, sleep restriction in normal weight adults reportedly leads to increased overall neuronal activation in response to food, particularly of brain areas involved in reward, including the putamen, nucleus accumbens, thalamus, insula, and prefrontal cortex (St-Onge et al., 2012). Obesity, in turn, interferes

Brain disease in obesity: dissecting the role of obesity from its confounders, hypertension, diabetes and the metabolic syndrome

Although obesity facilitates the evolution of dysglycemia, diabetes, hypertension and the metabolic syndrome, fat accumulation usually precedes the emergence of these sequels. Further, although concomitant realization of the presence of these conditions in cluster is not uncommon in humans, there is an actual lag time ranging between a few years to several decades between obesity and its sequels. A primary role for obesity can be therefore assumed on the basis of this chronological sequence

Conclusion

In conclusion, the evidence reviewed here suggests that excessive nutrition elicits early hypothalamic inflammatory effects, which likely disrupt the normal homeostasis of energy intake and expenditure as well as insulin secretion and sensitivity.

Structural changes in the hypothalamus, hippocampus and cortex may perpetuate these initially reversibly anomalies. Additionally, these structural changes may reflect genetic background as well as the added burden of the accrued fat mass with the

Author contribution

GS, YM and NS wrote, reviewed and edited the manuscript.

Conflicts of interest

GS, YM and NS declare that no conflicts no conflict of interest exists.

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    This study was funded by the Sagol Foundation.

    1

    These authors contributed equally to this work.

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