Science of Self-Preservation

Abstract

O besity is a major medical problem with a prevalence that is increasing at an alarming rate. 1 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 adiposity. 2 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. 3 Obesity is also responsible for increased morbidity from reproductive, skeletal, and gastrointestinal disorders, 4 as well as being negatively associated with psychological wellbeing and social functioning. 5 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. 6 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 synergistically 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. 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.

Obesity-induced Hypertension: Role of Sympathetic Nervous System, Leptin, and Melanocortins

“…Neurons that express POMC play a major role in regulating energy balance by reducing food intake and stimulating thermogenesis in experimental animals and humans (28,29). Located in the ARC of the hypothalamus, these neurons send projections to the PVN and lateral hypothalamus, where they release ␣-melanocyte-stimulating hormone, which in turn activates melanocortin 3 and melanocortin 4 receptors (MC3/4Rs) (Fig.…”

“…1). Other regions of the brain, especially the NTS, also contain POMC neurons and MC3/4Rs, which may be important in regulating energy balance (28,29).…”

“…Expression of the MC4R is especially dense in the PVN, although significant expression of the MC4R is also found in the NTS and the dorsal motor nucleus of the vagus (29). The PVN is an area of the hypothalamus that is important for control of autonomic function as well as food intake.…”

Molecular Changes Induced in Rat Liver by Hemorrhage and Effects of Melanocortin Treatment

“…17,18 By blocking the main pathophysiological mechanisms of organ damage, melanocortins would considerably extend the effective time-limit for blood reinfusion. 17,18 The antishock effect of melanocortins in experimental and clinical conditions have been recently highlighted by Corander et al 45 in an authoritative review aimed at spreading these relevant findings of basic science to clinicians.…”

“…17,18 Conversely, the short half-life of peptide molecules, including natural melanocortins, that are broken down readily in the body fluids, should not represent a limitation as several of the generated fragments are biologically active. 10 Finally, passage through the blood-brain barrier 10,12,44,45 and lack of receptor selectivity of melanocortins should not be problematic in short-term, acute treatments such as in hemorrhagic shock.…”