Obesity and Weight Management 1 PDF

10/29/2024 Energy expenditure Physical Activity: Exercise - Activities of Daily Living – Non-Exercise Activity Thermogenesis ✓Maintenance of basal metabolic pathways and autonomic nervous system-regulated homeostatic activities such as cardiac, respiratory and org...

10/29/2024 Energy expenditure Physical Activity: Exercise - Activities of Daily Living – Non-Exercise Activity Thermogenesis ✓Maintenance of basal metabolic pathways and autonomic nervous system-regulated homeostatic activities such as cardiac, respiratory and organ metabolism and function represent up to two thirds of daily energy expenditure in the majority of individuals. ✓Physical activity remains a most relevant source of energy expenditure, but it may account for only up to 25% of daily energy needs under western or westernized sedentary lifestyle conditions. 20 21 1  10/29/2024 22 ✓Indeed, the onset of the ongoing worldwide obesity epidemic has also undisputedly been paralleled by changes in routine activities of daily living, and lowering of energy expenditure associated with less intense activities such as walking and stair-climbing or even daily chores such as dish and clothes washing, all of which have been associated with increased obesity prevalence. ✓These observations indicate that sustained reduction of small amounts of energy expenditure may also contribute to energy-fat gain and ultimately obesity. 23 2  10/29/2024 ✓In more recent years the concept of non-exercise activity thermogenesis (NEAT) has been also introduced to indicate postural changes and involuntary movements such as fidgeting, that have been reported to account for up to 5% of daily energy expenditure. ✓NEAT may be regulated at the CNS level in experimental models and has been associated with variability of fat gain following sustained overfeeding in humans. ✓Obesity is commonly associated with reduced physical activity and exercise and the causal role of such impairment in obesity onset has been discussed above. 24 Metabolic pathways ✓As previously mentioned, the basal metabolic rate, and its underlying fundamental metabolic pathways regulating substrate oxidation and turnover for maintenance of ATP availability and cell and organ structure and function, accounts for the majority of energy expenditure in almost all of the general population. ✓Even moderate impairments in basal metabolic reactions may substantially negatively impact energy balance leading to long-term fat accumulation. ✓Heterogeneity in human obesity phenotypes with large variability associated with (among other factors) age, gender, ethnicity, lifestyle and comorbidities has made it impossible to identify universal associations between obesity itself and specific metabolic derangements. 25 3  10/29/2024 Mitochondria ✓Mitochondria are the site of substrate oxidation for ATP production in every tissue and organ. ✓ ATP production with high-energy phosphate bonds depends on utilization of electrochemical gradients generated across the mitochondrial membrane through substrate oxidative reactions. ✓Efficiency of ATP production is however never complete and partial energy dissipation with uncoupling from ATP production and heat generation is inevitable. 26 Brown adipose tissue (BAT) and Thermogenesis ✓Brown adipocytes substantially differ from their white counterparts since their primary function is to produce heat through fat oxidation in highly uncoupled mitochondria. ✓Brown adipocytes are indeed characterized by a high concentration of mitochondrial organelles whose membranes are enriched with uncoupling proteins (UCP) that generate heat by dissipating the transmembrane electrochemical gradient with limited ATP production. 27 4  10/29/2024 28 29 5  10/29/2024 ✓The discovery that BAT is abundant in adult humans has generated a major research avenue in obesity since activation of BAT may favor energy dissipation leading to negative energy balance and potentially to weight loss in obese individuals. ✓Most importantly, differentiation of white into brown adipocytes has been also described besides de novo brown adipogenesis from specific precursors, and factors favoring white adipocytes browning have also become primary potential targets for obesity treatment. ✓Cold exposure remains a major activator of BAT and white to brown differentiation, and catecholamine levels and signaling are among direct mediators of these effects. Negative modulators conversely include proinflammatory changes in tissue cytokines and hypoxia. 30 ✓It should be pointed out that exercise and nutrition are also emerging as regulators of BAT activation; exercise training and nutrients with anti- inflammatory and anti-oxidant capacity may indeed enhance BAT activation and thermogenesis, potentially by reducing inflammation or by enhancing angiogenesis. 31 6  10/29/2024 32 33 7  10/29/2024 Gut microbiota ✓The gut hosts a number of bacteria exceeding 10¹³ cells, and over the last two decades their role in the regulation of nutrient-host interactions has become increasingly clear. ✓The gut microbiome is considered an integral component of the gut- brain axis interacting with nutrients, enteral neuroendocrine cells and the autonomic nervous system; its physiological role impacts a number of fundamental homeostatic functions and pathways ranging from energy expenditure to intermediate metabolism to mood. 34 Genetic – Epigenetic Factors Genetic Background ✓Candidate genes for propensity to obesity obviously include the major regulators of eating behaviors, with particular regard to altered appetite homeostasis; associations have indeed been reported between, for instance, POMC polymorphisms and common obesity. ✓Taste perception has a partially genetic basis and the role of food preference in the regulation of eating behaviour and calorie intake is obviously relevant. 35 8  10/29/2024 Epigenetics ✓Besides its polygenic nature, it has become increasingly clear that epigenetic factors regulating gene expression at the transcriptional and post-transcriptional level play a major role in the onset of obesity by regulating energy balance even in the absence of gene sequence mutations and polymorphisms. ✓Epidemiological human studies and experimental models have indicated higher future obesity risk in individuals whose gestational life occurred during periods either of maternal starvation or of overfeeding, with risks transmitted to subsequent generations. 36 9