Neurobehavioral and neuroendocrine regulation of energy homeostasis

KEYWORDS:

• Energy homeostasis
• hypothalamus
• leptin
• obesity
• neurobehavioral
• neuroendocrine

The incidence of obesity is increasing worldwide and this is obvious even from childhood, reaching indeed epidemic proportions. This phenomenon is strongly associated with the consequent presentation of type 2 diabetes mellitus (T2DM), cardiovascular (CV) disease and CV mortality, as well as with the increase of various types of cancers [1]. The need for discovery of new therapeutic tools for this chronic medical problem has intensified the scientific efforts to address the pathophysiological complexity of the issue and to unravel the neurobehavioral and neuroendocrine regulation of energy homeostasis [2,3].

The human energy balance system is a complicated array of central nervous system (CNS) circuitry that actively integrates peripheral metabolic feedback signals. These signals send either energy deficit or energy abundance messages [2]. The major and most crucial center of hunger and satiety is located within the arcuate nucleus (ARC) of the hypothalamus, consisted of neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons, as well as cocaine and amphetamine regulated transcript (CART)/pro-opiomelanocortin (POMC) neurons. The NPY/AgRP neurons are responsible for the synthesis of neurotransmitters promoting orexigenic states, while the CART/POMC neurons for promoting anorexigenic states, mainly [3,4].

During fasting, gastric cells release ghrelin that stimulates the NPY/AgRP neurons. In turn, these neurons activate other ones in the lateral and perifornical hypothalamic areas, which contain orexins and melanin-concentrating hormone (MCH), while they inhibit oxytocin release from paraventricular (PVN) nuclei, in order to evoke acute feeding [2,5]. Ghrelin also provides orexigenic signals to the brainstem via the area postrema [5]. In postprandial state, various hormonal changes occur and favor satiety. After insulin secretion by β pancreatic cells, leptin release by adipocytes and incretins secretion (including glucagon-like peptide 1, GLP-1) by intestine cells, these hormones are conveyed into the ARC, where they activate CART/POMC neurons [2,6]. α-Melanocyte-stimulating hormone (α-MSH) is then released and binded to melanocortin receptors in other hypothalamic regions. These lead to acute hypophagic phenomena, as well as increased energy expenditure [3].

Energy homeostasis is controlled at long term too. Adipose tissue was considered in the past as a simple triglyceride storage organ, but nowadays it is very well known that acts as a proper endocrine organ. Adipose cells secrete leptin and its circulating concentrations are proportional to total body fat mass. Leptin acts as molecular signal for the CNS regarding the currently available amount of energy stored, presenting also abrupt changes between fasting and postprandial status [2,6]. The hypothalamus – pituitary – endocrine gland (adrenal, thyroid, gonadal and growth hormone) axes are also adapted in long term according to the energy amount stored in the body and this phenomenon seems to be mediated mostly by leptin too [2].

Several cortical and subcortical networks are also implicated in the eating process. Indeed, appetite is regulated by higher cognitive functions such as memory, emotions, reward and attention [3]. The energy homeostatic mechanisms and the regulation of food intake involves additional neurochemical systems, such as the endocannabinoid pathways which under glutamatergic activation or GABA (Gamma Aminobutyric Acid) -ergic activation may lead to hyperphagic or hypophagic effects [7]. The modulatory effects of such systems on energy homeostasis vary from person to person based on the individual hedonic value of food, which represents a specific and major aspect of feeding. The interplay of brain hedonic and homeostatic circuits has been also shown in the literature [2,7].

Additionally, food consumption seems to be temporally coordinated by the brain over the 24 h circadian cycle. A network of circadian clocks influence feeding and set daily windows that are most appropriate for food consumption [3]. A major clock is located in the hypothalamic suprachiasmatic nuclei (SCN), while secondary clocks are located in other hypothalamic and brainstem regions [8]. The master clock in the SCN represents a light-entrainable clock that tightly controls the sleep and wake cycle with hormonal and feeding rhythms [3]. Interestingly, experimental studies have provided evidence that ambient light perceived by the retina activates melanopsin-containing ganglion cells and provides photic cues that are able to synchronize the master clock with the external dark and light cycle [3,9]. A growing body of evidence supports that mistimed eating can lead to metabolic disturbances, while eating during normal active phases limits metabolic risks [3,10].

For each human, body weight is individually determined at a set point, according to genetic, neurocognitive and hormonal specific characteristics [2]. When environmental conditions are stable, body weight is maintained relatively constant around this set point. When external conditions change, adaptive changes regarding hormonal profile, energy intake and expenditure, as well as brain reactions take place, affecting appetite and energy expenditure [2,3]. Current treatments for obesity, such as liraglutide (a GLP-1 receptor agonist, GLP-1RA), lorcaserin, naltrexone/bupropion or phentermine/topiramate combinations, attempt to alter the adaptive inputs that affect this body weight set point [11].

Rapid advances on neuroendocrinology, neurobehavioral psychiatry along with the availability of novel neuroimaging techniques, such as functional Magnetic Resonance Imaging (fMRI) and Positron Emission Tomography (PET) scans, will allow for a further in depth investigation of the complicated biochemical and hormonal pathways of energy balance and homeostasis [2,3]. The more the physiological and pathophysiological knowledge of the field, the better for the discovery of advanced therapeutic tools for the management of obesity.

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Authors and peer reviewers on this editorial have no relevant financial or other relationships to disclose.

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The contents of the editorial and the opinions expressed within are those of the authors, and it was the decision of the authors to submit the manuscript for publication. This editorial was written independently; no company or institution supported the authors financially or by providing a professional writer.