Mark Fry

Obesity Research

Figure 2.  The arcuate nucleus of the hypothalamus is thought by many to be the key integrating centre for regulation of energy balance.  Activation of NPY/AGRP neurons tends to drive appetite and feeding, while activation of the melanocortin neurons inhibits appetite.  These neurons form a local circuit and project to second order neurons to regulare energy expenditure and food intake.


Source: Front. Neuroenergetics, 13 June 2013 | doi: 10.3389/fnene.2013.00006

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There is an immediate need to understand why we eat (AND OVEREAT).

     Obesity has become a global medical epidemic within the past 20 years, and it is now considered a greater threat to health and lifespan than is either undernutrition or infectious disease. In Canada, 59% of adults are overweight (BMI ≥ 25 kg/m2) or obese (BMI ≥ 30 kg/m2) 2 and the prevalence of overweight and obesity are rapidly increasing in Canadian children. Chronic health risks of obesity include type 2 diabetes, hypertension, atherosclerosis, cardiovascular disease, certain forms of cancer and orthopaedic injury. In 1997, the estimated direct and indirect Canadian healthcare costs due to obesity were $2 billion! These costs are expected to rise as the today’s obese children get older. It is well kown that the increasing prevalence of obesity in both wealthy and impoverished nations is related to an increased visibility and availability of tasty but fat-laden foods as well as a decrease of physical activity. However it is clear that the central nervous system (CNS) plays a significant role in the regulation of energy homeostasis. While making healthy changes to unhealthy lifestyles are clearly indicated for overweight and obese individuals, this approach may not be enough to help these individuals achieve a healthy weight: current data suggest that once an individual becomes obese, reversal of the condition is difficult in part because of “weight defending” changes in the brain. This prospect is especially daunting to people who have become overweight early in life, and are faced with the possibility of a long future of ill health due to their inability to achieve a healthy weight. My research program aims to understand the physiology of neurons that regulate energy homeostasis. This is important because understanding the neuronal circuitry that regulates energy homeostasis is a step towards developing more effective strategies to prevent and treat obesity.


Regulation of energy homeostasis: signals from the periphery.

     In mammals, the corticolimbic system is thought to mediate aspects of energy homeostasis such as procurement of food, sensory evaluation, social and hedonistic aspects of feeding. Additionally, the brainstem and hypothalamus are thought to play roles in aspects food intake such as detection of satiety signals, and the translation of information to control autonomic and neuroendocrine outputs. Satiety signals are circulating metabolites, hormones, adipokines and neuropeptides (such as glucose, leptin, ghrelin, insulin, amylin and glucagon-like-peptide) and are particularly important as they represent the primary means of communicating energy status from the periphery to the CNS. Recent work suggests that specific neurons of the arcuate nucleus of the hypothalamus (ARC) play a key role in detecting circulating satiety signals, however the role of these neurons is controversial because the ARC lies behind the blood brain barrier (BBB). Thus the ARC may be inaccessible to many satiety signals in the circulation that cannot pass the BBB. Therefore, a clear understanding of the mechanisms for detection of circulating satiety signals by the CNS is lacking.


Sensory CVOs: transducers of satiety signals across the BBB.

The sensory CVOs are small specialized midline structures that lack the BBB. They are found around the ventricular system of the CNS in vertebrates, and include the subfornical organ (SFO), the organum vasculosum of the lamina terminalis (OVLT), and the area postrema (AP). Sensory CVOs are characterized by extensive vascularization with fenestrated capillaries, and the presence of neuronal cell bodies surrounded by large extracellular spaces. These specializations allow solutes (such as satiety signals) to rapidly move across capillary walls, make contact with, and influence electrical activity of CVO neurons. Sensory CVO neurons also communicate with autonomic control centres such as the paraventricular nucleus of the hypothalamus (PVN), the lateral parabrachial nucleus (LPBN) and nucleus of the solitary tract (NTS). Thus, the sensory CVOs represent windows through which levels of circulating satiety signals may be communicated from the periphery to autonomic control centres.


The area postrema is well-recognized for its role in emesis, angiotensin II-mediated regulation of blood pressure, baroreceptor reflex and hydromineral balance. However, a key role for AP in regulation of energy homeostasis is now emerging. AP is recognized as an important site in the gut-brain axis for the action of the satiety signals such as cholecystokinin insulin, glucose, lactate, leptin, adiponectin, peptide YY, and ghrelin. In addition, lesioning of the AP in rats causes disturbances in food intake.


Recent work has established that SFO contributes to regulation of energy balance. Specifically, electrical stimulation elicits feeding in rats and SFO lesion reduces food intake. Our microarray data demonstrate that SFO expresses receptors for many satiety signals, including insulin, amylin, ghrelin, leptin, adiponectin, and melanocortins. Activation of these receptors modulates electrical activity of SFO neurons. Fasting regulates gene expression and electrical activity of SFO neurons. While a role in energy balance is recently recognized, the role of SFO in regulating cardiovascular output and hydromineral balance has been recognized for decades. For example, angiotensin II activates SFO neurons to stimulate drinking, an effect abolished by destruction of SFO. SFO neurons also regulate Na+ appetite, and meal-associated drinking18. Angiotensin II or electrical stimulation of SFO increases blood pressure, stimulates oxytocin release and elevates sympathetic outflow via connections to the PVN. Vasopressin, leptin and orexin all act at SFO to regulate cardiovascular output and sympathetic outflow. Together, these data indicate an integrative role for SFO in regulation of homeostasis.