The Hypothalamus: Central Appetite Regulation

Feeding and energy expenditure are controlled by complex neural networks distributed throughout the forebrain and brainstem. Homeostatic feeding behavior is integrated within the hypothalamus. 

Key peripheral signals of energy status such as gut hormones and adipokines either signal to the hypothalamus directly or indirectly via the brainstem and vagal afferent fibres. Adiposity signals such as insulin and leptin are involved in the long-term energy homeostasis, and gut hormones such as ghrelin are implicated in the short-term regulation of meal ingestion [1-3]. The Hypothalamus comprises various nuclei, of which the arcuate nucleus (ARC), the paraventricular nucleus (PVN), the ventromedial nucleus (VMN), the dorsomedial nucleus (DMN), and the lateral hypothalamic area (LHA) play a role in energy homeostasis.

Hypothalamic Orexigenic and Anorexigenic Neuropeptides
The ARC, known as the infundibular nucleus in man, is situated at the base of the hypothalamus. It contacts the peripheral circulation through semi-permeable capillaries in the underlying median eminence and is thus in an ideal position to integrate hormonal signals for energy homeostasis. In the ARC, there are two important discrete neuronal populations: Neurons coexpressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) stimulate food intake, whereas neurons coexpressing pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) suppress food intake. Both subpopulations project to the LHA and PVN, where they control the function of second-order neurons. In the PVN, two distinct subpopulations of neurons produce the anorexigenic (appetite-suppressing) neurotransmitters thyrotropin-releasing hormone, and corticotropin-releasing hormone. In contrast to this, in the LHA, two other subpopulations produce the orexigenic (appetite-stimulating) neurotransmitter orexin (hypocretin) and melanin-concentrating hormone (for review see [4, 5]).

Peripheral Hormones and Peptides Regulating Appetite
Leptin, predominantly synthesized in adipose tissue, inhibits NPY/AgRP neurons and stimulates POMC/CART neurons. Circulating leptin levels are directly proportional to adiposity in animals and humans. Insulin, which is produced in the β cells of the pancreas and rapidly secreted after a meal, binds to insulin receptors on the surface of POMC/CART neurons and activates them. The rise in circulating insulin in response to a glucose load is proportional to fat mass. Ghrelin, a hormone from the stomach, exerts a stimulating effect when binding at growth hormone secretagogue receptors on NPY/AgRP neurons. Circulating ghrelin decreases in response to chronic overfeeding and increases in response to chronic negative energy balance associated with exercise or anorexia nervosa. Whereas obese people usually have high plasma leptin, they have low plasma ghrelin (for review see [6]).

[1] Simpson et al., Arc Bras Endocrinol Metabol, 2009
[2] Stanley et al., Physiol Rev, 2005
[3] Suzuki et al., Endocr J, 2010
[4] Velloso et al., Neuroimmunomodulation, 2008
[5] Suzuki et al., Exp Diabetes Res, 2012
[6] Neary et al., Clin Endocrinol (Oxf.), 2004

By Charlotte Klein, PhD Alumna AG Neural Regeneration and Plasticity  
This article originally appeared 2012 in CNS Volume 5, Issue 4, Fat Gut or Fat Brain

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