Eat Well and Sleep Soundly, in These Two Good Health Abounds

Can Food Intake Influence Our Sleeping Pattern? There are few facts in life that are rock solid: food and sleep are among them. Everyone has to sleep - and obviously everyone has to eat. However, do these two fundamental pillars of bodily existence influence each other and if yes, in what way?

The WHY and WHEN of sleep is well studied and is known as the two-process-model of sleep-wake regulation. Process S is defined as a homogenic sleep drive which is generated by sleep inducing substances in the brain (WHY). Process C is the circadian clock, which serves as an internal time keeping device. It controls the timing of most of the processes in our body and by regulating “alertness”, it can influence WHEN we get tired.
The master clock in our brain (suprachiasmatic nucleus – SCN) can convey time cues (e.g., light-dark cycle) to the peripheral clocks which are ticking in almost every cell of our body. These in turn are thought to regulate local tissue physiology [1]. Now, this is where it gets interesting, since various metabolites can feed back onto the peripheral clocks and onto the SCN [2].
For instance, if food resources are restricted to a certain time of day, animals can go from being nocturnal to diurnal or vice versa on a behavioral level. This is also mirrored on the molecular level in tissues such as the liver [3, 4].

CHRONIC SLEEP DISRUPTION CAN LEAD TO OBESITY

 
Knowing how a system works means we can also trick it. For example, after a trans-continental flight, almost everyone suffers from jet lag. One way to adapt quicker is to eat meals corresponding to the local time, therefore already resetting our organ clocks to local time.
Conversely, if sleep rhythms and therefore eating rhythms are chronically disrupted, such as in shift workers, this can lead to obesity and other metabolic diseases [5].
All in all, in the hectic pace of modern life, we often neglect our body clocks concerning sleeping and food intake, thereby seriously endangering our health. As the medical psychologist Till Roenneberg said: "Time really is of the essence".

[1] Dibner et al, Annu Rev Physiol, 2010
[2] Morris et al, Mol Cell Endocrinol, 2012
[3] Damiola, Genes Dev, 2000
[4] Mistlberger, Eur J Neurosci, 2009
[5] Bass andTakahashi, Science, 2010

by Veronika Lang, PhD Alumna AG Kramer
This article originally appeared 2014 in CNS Volume 7, Issue 3, Nature vs Nurture

Can You Be Addicted to Food?

Clearly, food is something that most people really cannot go without. For some, it is the casual craving for carbohydrate-rich food after a long, frustrating day, while others just enjoy Schnitzel too much. But in recent years, a growing controversy has developed from the question of whether there is a darker, more sinister side to the pleasure of eating. As an old Jewish proverb has it, "worries go down better with soup". But can drowning your sorrows in soup become a problem someday?

The concept of “food addiction” has been around for significantly longer than current debates may make you believe (nearly 60 years, to be precise) [1]. Conceptually, its location on the etiological food chain ranks it somewhere between substance (e.g. alcohol) and behavioral addictions (e.g. gambling). One reason why food addiction offers such an intuitive appeal is its seamless correlation with the global rise in obesity levels. Additionally, it offers a psychological remedy (a sugar-coating, if you excuse the pun) that relieves the consumer from the responsibility to choose: who could be blamed for overeating if all those companies sell food that has been carefully developed to maximize palatability and reward? However, the story may not be that straightforward.

Source: Bay Hippisley

As always when in doubt, a look at animal models proves instructive. And indeed, there is a plethora of studies indicating that animals often fall prey to developing addiction-like behavioral phenotypes when offered access to food. However, not all foods are created equal. More specifically, it has been shown that highly palatable foodstuff (so, the goodies that you should be careful with... you know, the ones with health warnings on them) including a high proportion of processed sugar, fat or salt, are especially attractive.

While it is generally appreciated that eating highly toothsome food activates reward areas and neurochemical paths that are notorious for their implication in addiction, it has remained significantly less clear whether this follows the act of eating per se, or depends on food content (i.e. certain ingredients). For instance, while there is evidence to suggest that lab rodents may show withdrawal-like symptoms when going cold turkey on sugar [2], such behaviors have generally not been described in humans (except in a single case study) [3]. For fat and salt, results have even been less clear.

Fast food is equivalent to pornography

Besides, there are some semantic problems that the term “food addiction” has difficulties digesting. Essentially, while no one debates the existence of problematic eating behavior, for instance, during binge eating attacks, the concept of addiction implies that there is something in the food that gets people hooked. However, humans who overeat tend not to be picky about a particular nutrient, but rather binge on a wide range of available toothsome foodstuff. And normally, there is very little evidence to suggest that humans ingest specific food to satisfy their craving for specific ingredients, like sugar or fat, or that these chemicals are consumed in isolation [4].

Eating addiction may be more appropriate than food addiction

From this perspective, ”addictive eating behavior” may be a better term. What is more, at this point, it has become challenging to tell apart people with increased appetite/reduced satiety from people with real “eating addiction” [4]. Overeating may, therefore, be something that is the consequence of high and readily availability of food paired with a certain vulnerability, such as negative effect, emotion dysregulation, and stress susceptibility [5]. To satisfy criteria for an addiction, rather than a maladaptive, potentially harmful behavior per se, science still has to carry forward the necessary proof. In any case, medicalizing such behavior may have its benefits, as has been the case for smoking, which today receives undivided medical/therapeutic attention. 

And while “food addicts” have been able to exchange their experiences among peers in Food Addicts Anonymous since 1987, they might have been the victims of a simple misnomer. For all those in doubt, better try the quiz at http://www.foodaddicts.org/am-i-a-food-addict.


[1] Randolph, Q J Stud Alcohol, 1956
[2] Colantuoni et al, Obes Res, 2002
[3] Thornley and McRobbie, N Z Med J, 2009
[4] Hebebrand et al, Neurosci Biobehav Rev, 2014
[5] Gearhardt et al, J Law Med Ethics, 2013

By Helge Hasselmann, PhD Student AG Otte

This article originally appeared September 2015 in Volume 08 Issue 02 "Food for Thought"

The Role of BDNF in the Regulation of Body Weight and Energy Homeostasis

Brain-derived neurotrophic factor (BDNF) has been shown to play a crucial role in the regulation of neuronal development including survival, differentiation, and growth of existing and new neurons [1]. However, BDNF has also been identified as a key component of the hypothalamic pathway that controls body weight and energy homeostasis [2]. 

In the hypothalamus, BDNF mRNA is found in most of its functional units, i.e. paraventricular, arcuate, ventromedial and dorsomedial nuclei as well as the lateral hypothalamic area and the median eminence. Together with the hippocampus, the hypothalamus is the brain structure that contains the highest BDNF mRNA and protein levels. BDNF is largely coexpressed with its tyrosine kinase receptor trkB, suggesting that autocrine or paracrine mechanisms account for the general modality of BDNF action in the CNS (reviewed in [3]).
It has been shown that BDNF levels are low in obese people [4]. Interestingly, on the contrary, it has been found that serum levels of BDNF are significantly increased in obese women and significantly reduced in female patients with anorexia nervosa or bulimia nervosa compared to age-matched normal control subjects. Since BDNF has been described to exert a satiating effect, this may represent a long-term adaptation to counteract decreased caloric ingestion in anorexic and bulimic individuals or the increased one in obese subjects [5-7]. In humans, obesity and obesity-related symptoms have been associated with functional loss of one copy of the BDNF gene [8] and with a de novo mutation in the BDNF receptor Ntrk2 gene [9].
In animal studies, obese phenotypes are found in Bdnf-heterzygous mice associated with hyperphagia, hyperactivity, hyperleptinemia, hyperinsulinemia, and hyperglycemia [10, 11]. Both central and peripheral administration of BDNF decreases food intake, increases energy expenditure, and leads to weight loss [12, 13]. A recent study suggests that gene transfer of BDNF has a therapeutic efficacy in a mouse model of obesity and diabetes, leading to marked weight loss and alleviation of obesity-associated insulin resistance [14]. Knowledge of the exact molecular mechanisms of how BDNF regulates body weight and energy homeostasis is sparse and must be further elucidated.
 
[1] Hofer and Barde, Nature, 1988
[2] Wisse and Schwartz, Nat Neurosci, 2003
[3] Tapia-Arancibia et al., Front Neuroendocrinol, 2004
[4] Krabbe et al., Diabetologia, 2007
[5] Nakazato et al., Biol Psychiatry, 2003
[6] Montelone et al., Psychosom Med, 2004
[7] Montelone et al., Psychol Med, 2005
[8] Gray et al., Diabetes, 2006
[9] Yeo et al., Nat Neurosci, 2004
[10] Kernie et al., EMBO J, 2000
[11] Rios et al., Mol Endocrinol, 2001
[12] Pelleymounter et al., Exp Neurol, 1995
[13] Bariohay et al., Endocrinology, 2005
[14] Cao et al., Nat Med, 2009

By Charlotte Klein, PhD Student Medical Neurosciences, AG Neural Regeneration and Plasticity  

This article originally appeared December 2012 in "Fat Gut or Fat Brain"

Our Intelligence Depends on Our Weight

The prevalence of obesity (defined as a Body Mass Index equal to or greater than 30) is increasing around the world. Medical doctors and investigators have long wondered if there is a link between obesity and brain disorders. 

Interesting observations were made regarding the age of obesity onset. Higher fetal and postnatal levels of adiposity contribute to better brain development. However, obesity in mid-life - at ages 40-55 - and during late-life - at age 70+ - increases risk for dementia, independent of education, IQ or other factors.
But what are the mechanisms by which obesity influences the brain and cognitive function? Adipose tissue may contribute to cognitive decline in a variety of ways. This may happen indirectly because obesity can cause diabetes or hypertension, leading to cardio- and cerebrovascular diseases that are able to impair cognitive function.

A more direct link is via adipokines. They can cross the blood-brain barrier and cause structural abnormalities, such as increased amounts of white matter. Leptin, produced mainly by adipose tissue, has remarkable effects on neurogenesis, neuroprotection, and regulation of beta-amyloid levels. Hereby, it is able to improve cognition, delay age changes, and optimize learning and memory processes. However, patients with common obesity can not benefit from elevated leptin levels because they show increased leptin resistance. A number of mechanisms, including the leptin-stimulated phosphorylation of Tyr(985) on LRb and the suppressor of cytokine signaling 3, attenuate leptin signaling and promote a cellular leptin resistance in obesity [1]. Another important multifunctional hormone is ghrelin. It is produced in a wide variety of tissues associated with the progression of obesity and metabolic syndrome. Acyl-ghrelin may modulate specific molecular intermediates involved in memory acquisition and consolidation through promotion of synaptic plasticity. In patients with Alzheimer's disease, the ghrelin autocrine/paracrine loop in the temporal lobe was found to be dramatically disrupted [2].

Furthermore, the brain can be susceptible to higher adiposity due to basic underlying differences in the structure and function of the nervous system. Studies using MRI have identified a number of brain regions potentially related to adult human obesity. These are mostly prefrontal areas which are different in gray matter density in obese and lean individuals. Higher BMI has also been related to a higher rate of brain atrophy using serial MRI [3].
It looks like exercise and maintaining a healthy weight are necessary not only to keep ourselves fit, but also to keep our brains functioning well.

[1] Paz-Filho G, Int J Clin Pract, 2010
[2] Gahete M et al., Peptides, 2011
[3] Enzinger C et al., Neurology, 2005

By Natalia Denisova, MSc Student Medical Neurosciences  

Tis article originally appeared December 2012 in Volume 05, Issue 04, Fat Gut or Fat Brain

The Fat Brain or the Fat Gut

Today is world obesity day. While we featured already several articles about obesity (Big, Bigger, Obese), dieting (Dieting and the Brain), other ways to loose weight (HCG Injections for Weight Loss) and ideal nutrition (How to Eat Smart), today's article gives a great introduction about the relationship between the brain and the gut and how  it is associated with obesity
 

Obesity - A Burden to Modern Society
Obesity has become one of the major challenges to human health worldwide, most markedly in industrialized countries. In Germany, about half of the adult population is classified as being overweight or obese, with a higher percentage in males (60 %) than in females (44 %) (GEDA, Robert Koch Institute, 2010). Overweight or obese individuals have a high risk of developing comorbidities, including type II diabetes mellitus, hypertension, and coronary heart disease, the most common cause of premature mortality in the obese population.
Body mass stability largely depends on the perfect coupling between caloric intake and energy expenditure [1]. Obesity is a state in which energy intake chronically exceeds energy expenditure. Even a subtle mismatch (less than 0.5 %) in caloric intake over expenditure is sufficient to cause weight gain [2]. The rising prevalence of obesity is likely due to contemporary environmental and lifestyle factors, such as overconsumption of energy-dense food and reduced requirements for physical activity in comparison with the lifestyle of our hunter-gatherer ancestors.

Who is to Blame?

The Brain and the Egg-and-Chicken Principle
The role of the hypothalamus in the regulation of feeding and energy balance was first highlighted by lesion studies in rodents [3, 4]). This brain area comprises specialized neurons that modulate food intake by acting to either stimulate or -suppress appetite (see article by Charlotte Klein). Because of this, the hypothalamus has been determined as a key component in the regulation of metabolic homeostasis "integrating information regarding the body's internal environment and orchestrating a series of coordinated endocrine, autonomic, and behavioral responses that maintain metabolic homeostasis" [5]. However, while great efforts have been made to understand how the brain controls our desire to feed as well as the processes underlying the balancing of energy intake and expenditure, little is known about how the structure and organization of the hypothalamus are altered by obesity. The question still remains whether obesity is a consequence of hypothalamic dysfunction or if it even causes changes in the functionality of the hypothalamus, as has been observed in rodent studies of obesity.

The Role of the Intestinal Tract
Not only the brain, but also the gut takes part in the regulation of appetite and fat storage. There is a long list of factors that originate from the gastrointestinal system and play a role in the management of energy balance by regulating the satiety feeling and thereby, food intake. The main ones are ghrelin, cholecystokinin, peptide YY, pancreatic peptide, glucagon-like peptide 1, and oxyntomodulin (for reviews [6] and [7]).
But these are not the only 'gut factors' controlling energy homeostasis of our organism. Recently, another key player was added to the regulators of our energetic well-being: the intestinal microbiota. These microorganisms, living in our gastrointestinal tract, have coevolved with their human hosts through ages, becoming important for many processes in the human body (see article by Sophie Schweizer). Actually, one could say, we are more microbes than man, because the number of bacterial cells in our intestines exceeds the number of the human cells in our body. Would you believe that the intestinal bacteria have an estimated mass of 1 to 2 kilogram? [9]
It has been shown in studies in mice and humans that the composition and function of microbiota may play a crucial role in the regulation of fat storage and lipid metabolism (more to be read in the article by Jana Foerster). Commensal microorganisms also seem to play a role in some obesity-related comorbidities, for example type II diabetes. Jens Nielsen, at the METAHIT conference in Paris in 2012, even stated that: "Gut microbiota species abundance is a more accurate predictor of type II diabetes than waist-to hip ratio".
Very interesting data have been produced by studies using germ-free mice (animals raised with zero contact to bacteria, see also article by Katarzyna Winek). These mice are leaner than their wild-type littermates, who have about 40 % more fat tissue. After colonization with bacteria from conventionally raised mice, the previously germ-free animals start to gain weight despite decreasing food consumption [10]!

Then, is it the Microbiota Issue?
It is good to take care of our microbial friends: A recently published Nature paper from the group of Martin Blaser describes how subtherapeutic doses of antibiotics can influence the metabolism. They created an adiposity model by introducing antibiotic low-dose treatment. Investigated animals had changes in their microbiome composition and alterations in many metabolic pathways [11]. Another interesting study showed decreased diversity and overall number of gut microbiota in the populations with a high prevalence of severe obesity and its related diseases. Additionally, the most effective obesity treatment (a surgical intervention by gastric banding, sleeve gastrectomy or gastric by-pass, used only in the most severe cases, i.e. BMI ≥ 40) not only leads to improvement in the inflammatory and hormonal status, but also to changes in the gut microbiome. However, up to now only limited data have been produced [12].

Better be Good to Your Commensal Bacteria!

We may say with certainty that we have not yet unraveled all the connections between the gut, the microbiota and the brain or their particular roles in the pathogenesis of obesity, but understanding this signaling in obesity and associated diseases is of huge importance. Recent discoveries and detailed characteristics of pathways involved in the pathogenesis may lead to more effective therapies with multiple targets. It is probably neither the brain nor the gut alone, but a complex interaction of both to blame for round shapes.


[1] Morton et al., Nature, 2006
[2] Hagan and Niswender, Pediatr Blood Cancer, 2012
[3] Tepperman et al., Yale J Biol Med, 1943
[4] Stellar, Psychol Rev, 1954
[5] Williams et al., Eur J Pharmacol, 2011
[6] Small and Bloom, Trends Endocrinol Metab, 2004
[7] Suzuki et al., Exp Diabetes Res, 2012
[8] Murphy and Bloom, Exp Physiol, 2004
[9] Forsythe and Kunze, Cell Mol Life Sci, 2012
[10] Bäckhed et al., Proc Natl Acad sci U S A, 2004
[11] Cho I et al., Nature, 2012
[12] Aron-Widnewsky et al., Nat Rev Gastroenterol Hepatol, 2012

By Charlotte Klein and Katarzyna Winek, PhD Students Medical Neurosciences  

Tis article originally appeared December 2012 in Volume 05, Issue 04, Fat Gut or Fat Brain

HCG Injections for Weight Loss - Tricking The Brain or Tricking Your Wallet?

Spring is coming, and so is the urge to get fit and healthy. We know that the best way to get fit and healthy is through exercise and optimal nutrition, but wouldn't it be nice to reach your goals faster with the help of medicine?

A growing trend in popular culture has been the use of HCG (human chorionic gonadotropin) as treatment for obesity. First touted in the early 50’s by Dr. Albert Simeons as a miracle cure that, in combination with a strict 500 kcal/day diet, leads the body to preferentially burn stored fat rather than muscle, while tricking the brain into feeling neither hungry, irritable, nor fatigued. In a 1954 paper, Simeons claims to have treated 500 patients for 40 days, all of whom lost between 9-14 kg while maintaining a sense of well-being [1]. But what is HCG exactly, and is this regimen healthy or even effective?

Fat Profits by Mike Licht via Flickr

HCG, a commonly occurring hormone during pregnancy, can be extracted from the urine of pregnant women and is approved for the treatment of various forms of infertility [2]. However, many online pharmacies have begun marketing it for weight-loss, infusing it with vitamin B12, and charging an astronomical 200-250€ for a month’s supply [3].
Still, international authorities including the FDA have issued statements that HCG provides no benefit in the treatment of obesity, which is unsurprising given its paucity of clinical trials [1]. Authors of a 1995 meta-analysis of 24 clinical trials also concluded that “there is no scientific evidence that HCG is effective in the treatment of obesity; it does not bring about weight loss or fat redistribution, nor does it reduce hunger or induce a feeling of well-being” [2]. In fact, an alarming number of studies have reported adverse effects of the hormone including blood clots, headaches, restlessness, depression, and dizziness [1]. Last year, a case report was published on a 32-year-old female who suffered a manic episode as a result [4].

HCG PROVIDES NO SOLUTION TO TREAT OBESITY

The conclusion? A diet of 500 kcal/day will induce significant weight loss, but HCG neither “tricks” the brain nor augments the diet’s overall effect. Furthermore, it fails to provide the body with necessary nutrition and can lead to deficiencies and imbalances that negatively impact the brain.

[1] Robb-Nicholson, Harvard Women's Health Watch, 2010
[2] Lijesen et al, Br J Clin Pharmacol, 1995
[3] nuimagemedical.com
[4] Sanches et al, Bipolar Disord, 2014

by Kristina Kelly
This article originally appeared September 2015 in Volume 08 Issue 02 "Food for Thought"