How Melanocortin Action in the Brain Modulates Body Weight, Blood Pressure, and Ischemic Damage
Introduction
Obesity is a major medical problem with a prevalence that is increasing at an alarming rate. It remains a major risk factor for cardiovascular disease, metabolic diseases like type 2 diabetes mellitus, and certain cancers. There is also an established link between obesity and hypertension. The Normative Aging Study found that adiposity is significantly positively associated with both systolic and diastolic blood pressures and that up to two thirds of hypertension cases are associated with excess adipose tissue. In addition, evidence from the Framingham Offspring Study suggests that obesity may account for up to 78% of hypertension in men and 64% in women. Obesity is also responsible for increased morbidity from reproductive, skeletal, and gastrointestinal disorders, as well as being negatively associated with psychological well-being and social functioning.
The simple principle that obesity can arise only when energy intake exceeds energy expenditure remains undisputed. Furthermore, rapid changes in the availability, composition, and consumption of energy-dense food, coupled with a downturn in physical activity levels in all aspects of daily life, have undoubtedly contributed to the recent rises in the prevalence of obesity worldwide.
However, in the midst of these dramatic societal changes, many people remain lean. Indeed, the fact that most healthy adults maintain a steady body weight over many years despite huge variations in daily energy intake and expenditure is powerful testament to a system that is under tight homeostatic control. The last 15 years have seen a huge increase in our knowledge of the molecular players that underpin these regulatory systems. Many of the seminal observations in this field have come from obese animal models, both naturally occurring and genetically modified, but have combined synergistic with data from human genetic and physiological studies. We now understand that contained within the brain are a number of signaling systems that are crucial for the central nervous system to sense peripherally derived signals of both long-term energy stores and more short-term changes in energy expenditure.
One of the most critical of these central pathways is the central melanocortin system, a pathway primarily within the hypothalamus and based around the actions of a family of small peptides (the melanocortins). In this review, we highlight the basic anatomic and functional architecture of the central melanocortin system and review some of the data surrounding the potential physiological roles of the melanocortin peptides (Melanotan II). We also describe the convergent data from animal and human studies that have recently given some tantalizing hints into the link between obesity and hypertension. Finally, we discuss evolving, primarily preclinical, data that indicate that melanocortin signaling through the central nervous system may play a part in limiting tissue damage from inflammation and ischemia.
Brain
The synthetic melanocortin analog NDP-MSH has recently been shown to have a neuroprotective role. Induced transient global cerebral ischemia by bilateral occlusion of common carotids resulted in active inflammation and neuronal damage within the hippocampus, with peripheral administration of NDP-MSH inhibiting cytokine expression and reducing histological damage within this brain region. Further pharmacological exploration of this pathway indicated that MC4-R but not MC3-R activation was responsible. Similar results have been seen in other species,62 and as in hypovolemic and septic shock, it now appears that the vagus nerve is important in mediating the protective effects of the melanocortins against cerebral ischemia. Focal cerebral ischemia in rats induces a cerebral and hepatic inflammatory cascade that can be suppressed by melanocortins.
Therapeutic perspectives
A plethora of data has accrued over the last 15 years on the structure and function of melanocortin receptors, particularly with respect to their role in energy homeostasis. With the prevalence of obesity continuing to rise worldwide, the ability to modulate the activity of a surface receptor like MC4-R becomes a tantalizing pharmacological goal. However, getting a "clean hit" with a drug that tackles obesity by acting on central receptors is no mean feat. Consider the cannabinoid system, which, just like the melanocortin system, has a central action in the regulation of food intake and is widely expressed in the central nervous system. The early clinical promise of rimonabant, an antagonist at the cannabinoid 1 receptor, was dashed when unwanted off-target actions led to problems that resulted in the withdrawal of the drug. So it may be for drugs that act as melanocortin agonists.
Long before the melanocortin receptor system was characterized, central administration of a melanocortin agonist was reported to evoke a bizarre systemic syndrome of stretching yawning. Move forward 50 years, and melanocortin agonists designed primarily as an agent to reduce food intake and decrease body weight are, perhaps unsurprisingly, reported to cause similar systemic effects.39 Such findings will, at the very least, inject a note of caution into the active pursuit of these agents as effective and safe weight loss agents. However, a drug effect is only an adverse effect if it is unwanted, either in its direction or in it magnitude. A drug that causes an increase in blood pressure is going to be hard to let pass as a long-term treatment in a patient population likely to be burdened with other cardiovascular risk factors, but in an acute life-threatening emergency, this rapid-onset effect may be far more helpful. Indeed, the history of melanocortin pharmacology has already gone through a similar cycle of serendipity whereby an "unwanted side effect" of penile erection after melanocortin agonist administration led to this class of drugs being developed as a treatment for erectile dysfunction.
There is still pharmaceutical industry interest in designing drugs to perturb melanocortin signaling, with high-throughput screening of compounds, in silico modeling, and the development of novel, non-peptide, low-molecular-weight organic compounds all ongoing. However, there is still much to do before melanocortin-derived agents, whether modified peptides or chemically distinct small molecules, make it into the clinical arena. There may be a need to design an agent that goes beyond simple receptor specificity and that also has tissue, or in the case of the brain, region specificity.
It is also clear that the roles of melanocortins in pathways controlling energy balance have been demarcated more clearly than those relating to cardiovascular disease. The data on melanocortins and ischemic damage are derived almost entirely from experimental animal models, and there are no substantive data linking melanocortins with the pathogenesis of atherosclerosis. However, we suggest that the recent proof-of-concept studies highlighting the beneficial effects of melanocortin on limiting tissue damage in cases of ischemia and inflammation merit further attention. We look forward to following the evolving story of how perturbations in melanocortin signaling, whether from congenital deficiency or pharmacological manipulation, influence cardiovascular pathophysiology.
Summary
The diverse roles of the melanocortin system can be viewed as crucial components of the body’s defense mechanisms, whether by limiting ultraviolet light damage to the skin, fueling the drive to eat when energy stores are low, or fine-tuning the inflammatory response to physical trauma to minimize tissue damage. Our knowledge of melanocortin biology continues to evolve and develop. The importance of key parts of the system in the control of energy homeostasis remains unchallenged, with, for example, common variants near MC4-R now being implicated in influencing fat mass, weight, and obesity risk at the population level. Furthermore, although not discussed in this review, there is an increasing body of work highlighting the role that increased melanocortin activity has in the pathogenesis of cachexia.
With this ongoing expansion of knowledge, it is surely only a matter of time before pharmaceutical agents derived from these simple peptides come of age. However, whichever niche these drugs eventually occupy, clinicians need to remain mindful of this evolving sphere of influence and remain attuned to potential effects, good and bad, in tissue and organs distant from the primary target.
Role of central serotonin and melanocortin systems in the control of energy balance
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK
Abstract
Body weight homeostasis is critically dependent upon the convergence and integration of multiple central and peripheral signalling systems that collectively function to detect and elicit physiological and behavioural responses to nutritional state. To date, only a minority of these signals have been pharmacologically targeted for the treatment of human obesity. One signal that has been effectively manipulated to reduce body weight is the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT); however, the relevant downstream signalling pathways are incompletely understood. Recently, the melanocortin system, a nexus for multiple modulators of energy balance, has emerged as one key mediator of serotonin's effects on appetite. Here we review the serotonin and melanocortin systems with reference to their roles in energy balance and discuss the evidence that the two systems are functionally linked.
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