1. Introduction: The current environment especially in Western societies promotes increasing consumption of calories along with a relatively sedentary lifestyle thus fueling the global obesity epidemic. Body weight is regulated by complex interaction of genes that promote energy storage along with environmental factors that promote enhanced energy intake and reduced energy expenditure. This obesity promoting environment makes it difficult for many people to sustain weight loss for long periods of time and adequately maintain healthy lifestyle habits. Obesity can overall have many devastating effects on human health such as increased tendency to develop high blood pressure, cardiovascular problems and strokes.
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2. Metabolic responses to attempts to sustain weight loss: Any change in the amount of energy stored as adipose tissue reflects a difference between energy intake and energy expenditure through metabolic and physical work. Thus, maintenance of reduced degree of body fatness requires careful attention to energy intake and energy expenditure during the lifetime of the individual. The inability of weight-reduced people to sustain weight loss reflects the complex actions of various metabolic pathways, the neuroendocrine system and the autonomous nervous systems as described by Rosenbaum M. and Leibel R.L. (2010). The Central Nervous System (CNS) mechanisms for fat storage are the same in lean and in obese individuals. There is a complex system of regulation in the CNS for the coordination of energy intake and energy expenditure. This system for energy coordination is mediated by a variety of complex signals from adipose tissues, gastrointestinal tissues, by endocrine mechanisms and integrated in the liver and CNS.
3. Energy expenditure: Energy expenditure is expressed as the sum total of Resting Energy Expenditure (REE), thermic effects of digestion and Non-Resting Energy Expenditure (NREE) in a 24-hour time frame. REE takes into account vital cardiovascular functions and maintenance of ion gradients at resting level. REE accounts for approximately 60 percent of total energy expenditure (TEE). The thermic effects of feeding account for approximately 5-10 percent of TEE. The remaining 30-40 percent of total energy expenditure (TEE) can be attributed to NREE that is physical activity above resting energy level. After weight loss, the Resting Energy Expenditure (REE) is believed to show only a slight decrease and the thermic effects of digestion do not change significantly. However, NREE is the component of energy expenditure that changes most significantly after weight loss. This is consistent with the requirement of physical activity in maintaining weight loss. In weight reduced subjects, NREE can account for approximately 85-90 percent of the decline in TEE. Leptin is a hormone which plays an important role in feeding and consequently energy intake. On leptin administration to weight reduced subjects, the 24 hour energy expenditure (TEE), Non-Resting Energy Expenditure (NREE) which were previously decreased are reversed by leptin administration as shown in Table 1 Rosenbaum M. and Leibel R.L. (2010). Skeletal muscle work efficiency which was previously increased in weight reduced people is also reversed on leptin administration.
4. Neuroendocrine function: Maintenance of reduced body weight involves increased activation of the Hypothalamus-Pituitary-Adrenal axis (HPA) and reduced activation of the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-gonadal axes. According to Rosenbaum M. and Leibel R. (2010) these neuroendocrine changes may be centrally co-ordinated by the pro-opiomelanocortin (POMC)- melanocortin-melanocortin 4 receptor (MC4R) pathway by integrating the effects of energy expenditure and energy intake that play a vital role in body weight regulation. The neuronal tracts of this POMC-MC4R pathway interacts with the Autonomous Nervous System (ANS), neuroendocrine axes and cortical tracts related to food intake. The hormone leptin plays an important role in regulating body weight but it shows different effects in mice and in humans. In studies done on mice leptin-deficient or leptin-resistant mice are hypometabolic and severely obese. This is unlike the effect that leptin has in humans. In humans, energy restriction and maintenance of reduced body weight are associated with decreased concentrations of circulating leptin. Thyroid hormones also play a role in regulating energy expenditure. People with low-thyroid function tend to be hypotensive, lethargic and gain weight. On the other hand, people with high thyroid function tend to be hypertensive, tachycardic and have decreased body weight.
5. Autonomous Nervous System (ANS) function: Both the sympathetic and parasympathetic branches of the Autonomous Nervous System (ANS) link important biochemical signals that regulate energy stores and energy expenditure. The sympathetic branch directly regulates feeding mechanisms by having an effect on the thyroid gland causing it to secrete thyroid hormone. In weight- stable individuals, daily excretion of norepinephrine in urine account for variance in energy expenditure. Increase in activity of the parasympathetic nervous system branch also has effects on energy expenditure by causing decreased heart rate and decrease in REE. According to the authors Rosenbaum M. and Leibel R.L. (2010), the Autonomous Nervous System (ANS) and particularly the sympathetic nervous branch may account for the hypometabolic state by directly having effects on skeletal muscles and indirectly regulating circulating thyroid hormones. Thus, changes in ANS activity may be a link between changes in energy expenditure and neuroendocrine function. Overall, maintenance of reduced body weight is associated significant decreases in the sympathetic nervous system tone and increases in the parasympathetic nervous system tone.
6. Brown adipose tissue (BAT): Brown adipose tissue (BAT) plays an important role in thermogenesis in small mammals but its role in humans other than during the neo-natal stage for heat-regulation is not clearly understood. BAT tissue is special in that it allows uncoupling of mitochondrial substrate oxidation and ATP production thereby releasing the energy from fatty acid oxidation as heat. Unlike white adipose tissue, BAT is capable of this uncoupling since it contains an uncoupling protein known as UCP1 that is not found in white adipose tissue. The authors Rosenbaum M. and Leibel R.L. (2010) speculate that unexplained changes in REE following weight loss may be caused by changes in BAT activity in adults. Positron Emission Tomography (PET) analysis of BAT by fluorescent labelled dyes such as 2-[18F]-fluoro-2 deoxy-glucose (FDG) help to map BAT anatomically in adults but are not necessarily indicative of its actual thermogenic function or activity. Increased glucose uptake by BAT is considered to better reflect increased BAT metabolic activity and thermogenesis.
7. Metabolic responses to attempts to sustain weight gain: The long-term relative constancy of body weight suggests that energy intake and expenditure vary sufficiently in order to maintain a relatively stable balance of energy stores. However during dramatic weight-loss, this balance of energy regulation and energy stores are disrupted. The mechanisms that involve weight gain and weight loss involve the same body systems but the pathways do not necessarily function as mirror images of each other. Maintenance of elevated weight involves significant increases in circulating concentrations of the thyroid hormones T3 and T4 and circulating hormone leptin. As a result of elevated weight maintenance, TEE and NREE also increase while the parasympathetic nervous system tone and skeletal muscles work less efficiently. Overall, the prevalence of obesity in humans leads the authors Rosenbaum M. and Leibel R.L. (2010) to suggest that body fatness is regulated more vigorously than body thinness and opposition to sustaining weight loss is much more prevalent than metabolic opposition to weight gain.
8. Leptin in energy homeostasis: Leptin is derived from adipocytes and it is found circulating in larger quantities in heavier people who are weight stable than in leaner people. When fat storage is reduced in humans, there is less circulating leptin in the body and this has a net effect of stimulating food intake. During weight loss, circulating leptin is inversely correlated with hunger ratings and this is independent of the amount of weight or body fat lost. Furthermore, leptin suppresses food intake by increasing the production of the anorexigenic neuropeptide products and reducing the production of the orexigenic peptides of the POMC pathway.
Studies show that leptin administration to weight reduced individuals reverses decreased energy expenditure and increases skeletal muscle efficiency which is characteristic of the weight reduced state. The CNS components may perceive energy homeostasis as a state of relative leptin deficiency. Induction of weight-loss in humans (obese and lean) requires doses of leptin that result in plasma concentrations over 10 times that of normal. Pharmacotherapy intervention to activate the leptin signaling pathway may help formerly obese people maintain sustained weight loss.
9. Conclusion: Maintenance of sustained weight loss is a complicated process involving the actions of several metabolic pathways and body systems regulated by the CNS. The neuroendocrine mechanisms, autonomous nervous system, circulating hormones such as leptin and thyroid hormones all play important roles in regulating fat storage in the body. The balance between energy intake and energy expenditure helps regulate and maintain body weight. Excess energy that is not expended by metabolic or physical work is converted into fat storage in the body. Maintaining a reduced body weight is much harder in the long run than losing that body weight in the first place. Adipocyte derived hormone leptin functions to oppose sustained weight loss. Pharmacological manipulation of the leptin signaling pathway may help maintain sustained weight loss in formerly obese people. It is also very important to understand obesity as a disease in which the human body actively opposes a cure in the long run.
REFERENCE:
Rosenbaum M. and Leibel R. (2010) Adaptive thermogenesis in humans, International Journal of Obesity, Volume 34, pp. S47-S55.
