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Textbook of Obesity

Unit Two

QuestionAnswer
3 main points to studying genetics of obesity 1)understand the evolutionary basis 2)To identify genes that can be used as prognostic factors 3)To identify genes that monitor the safety or efficiency of treatments
The trouble with iding genes using parental adiposity levels are better. Its easy to predict obesity given current population levels. No prevention strategy that is at work.
How do we study genetics of obesity? Animal models and human studies.
animal models-single gene loss of function mutations Removing a gene.
animal models-Mutations without loss of a gene. (knocking mice) adding a gene or replacing with a mutated form.
Polygenic models investigators are locating many treatments.
Human studies-Measured genotype approach doing a direct measurement and seeing the differences.
Human studies-phenotype variances How much the gene is affected by the environment.
Designs of human studies Family link (maybe they share the same environment)
Design of human studies-Twin studies maybe a genetic link or environment link.
Design of human studies-Adoption studies having same traits as the biological family or adoptive family.
Design of human studies-Admixture studies When societies /cultures come together and determine mixture of genes.
Findings of genetic studies roughly 70% is associated with genetics in obesity. Twin studies show 50% to 90% variation in BMI.
Contributions form environment Heritability estimates of 60-70% imply that environmental factors explain the remaining 30-40% of the variance in BMI.The more active twin of a twin pair is generally less obese.
Contributions to environment 2 Immigrants to US usually show marked differences of obesity compared to their counterparts who stayed in their native country
Contributions to environment-Thrifty genotype hypothesis extra fat storage if you’re going through a starving period. the abilty to have more fat storage. Showing how the environment can influence how your genes can mutate and change.
Contributions to environment-Intrauterine and maternal effects The environment in the womb.
Specific genes-Monogenetic Obesity Rare severe, start in childhood.
Specific genes Polygenic Obesity- Many factors contribute -multiple genes, environmental behavior and lifestyles.
Monogenic Obesity-Leptin and Leptin Receptor There is a system that signals the brain about the amount of adipose reserves Leptin inhibits feeding and increases thermogenesis
Monogenic Obesity-Proopiomelanocortin Increasing levels of leptin stimulate hypothalamic synthesis of α-MSH to MC4R promotes energy expenditure and decreases food intake
Polygenic Obesity Many genes have been studied and are thought to be associated with obesity. They do not necessarily indicate causal relationships between genes and traits.
Polygenic Obesity cont... Do not yet understand the biological mechanisms or pathways through which most of these genes affect obesity-related trains
The new genetics-Gene-gene interactions one gene depends on the other.
The new genetics-gene-environment interactions Although certain genes may increase one’s chances of becoming obese, changes in behavior or the environment may reduce the chances of developing this condition
Novel Approaches to Genomic Studies Transcriptomics, Epigenetics, Copy number variation.
Transcriptomics Aka genome-wide expression profiling Looks at expression levels of mRNA to understand the functional role of genes, the regulation of gene expression in various cells and states, and how gene expression is affected by various treatments and diseases
Epigenetics Study of variations in an individual’s phenotype due to diffences in genetic expression Genomic imprinting
Copy number variation Differences in the number of copies of large stretches of DNA among individuals
Macro level Government regulation, food industry incentives, school lunch programs, advertising campaigns
Intermediate level The environment in which we live and work
Micro-level Making a choice (i.e. fresh fruit or sugary snack)
Eating Environment Ambient factors Atmosphere Effort of obtaining food Distractions that may be taking place Eating with others
Food Environment Factors that directly relate to the way food is provided or presented Salience Structure Size Shape Stockpiles
Consumption Monitoring: Unawareness of how many food-related decisions we make
Consumption Norms: Unwillingness to believe consumption norms influence us
Why do environmental cues make us overeat? Environmental cues bias consumption norms AND We underestimate the calories in large portions
Environmental cues bias consumption norms People often rely on consumption norms to help determine how much they should eat Larger food packages, larger portion sizes and larger dining ware suggest that it is appropriate and normal to serve larger sizes
We underestimate the calories in large portions A major determinant of how much people eat is often whether they deliberately monitor or even pay attention to how much they eat Ability to monitor or estimate how many calories we eat becomes increasingly less accurate as portion size increases
Are we aware of the consumption norms that have led us to overeat? Monitoring our food and drink intake is mundane and a nuisance. Typical person makes 200 – 300 food-related choices a day Obese individuals make the most decisions
How the food environment encourages mindless eating Salient food promotes salient hunger Structure and perceived variety can drive consumption Size of packages and portions suggest consumption norms Stockpiled food is quickly consumed Serving containers that are wide or large create consumption illusio
How the eating environment stimulates consumption Atmospherics influence eating duration Lighting Odor Noise and the Sound of Music Increased effort decreases consumption Socializing influences meal duration and consumption norms Distractions can initiate, obscure, and extend consumption
Atmospherics Lighting Odor Noise and the Sound of Music
Increased effort decreases consumption
Socializing influences meal duration and consumption norms
Distractions can initiate, obscure, and extend consumption
Additional environmental Contributing Factors Greater availability of high energy-dense foods and sugar drinks Built environment Limited access to healthy, affordable foods No safe or appealing play zones
Adipose Tissue Defined adeps” – Latin word for fat A specialized, loose connective tissue in which the adipocyte is the defining cell type Two histologic forms found in mammals: white adipose tissue brown adipose tissue
White Adipose Tissue Primary storage site for fat Comprises the largest portion of adipose tissue.Distributed in depots throughout the body. Subcutaneous Visceral organs (kidneys, heart, intestines) Certain blood vessels (coronary arteries) Bone marrow
Brown Adipose Tissue Heat-producing (thermogenic) tissue “Baby Fat” Have been identified in healthy adults (in neck/upper thorax areas
Heterogenous Distripution of Adipose Tissue Fat distribution between men and women are not uniformly observed.However, upper body fat is more commonly seen in men and lowe-body fat is more common in women.The exact mechanisms for these differences in distribution is largely unknown.
Higher risk for dz associated with apple shape. Higher risk for CVD, HTN, and DM associated with intra-abdominal fat accumulation. Apple.
Adipocytes Aka Adipose cells Specialized cell that contain a large droplet of lipid (aka fat) Fat droplet squeezes the nucleus and other cell structures to the side of the cell Size of the adipocyte is largely determined by the size of the lipid droplet
Pre-Adipocytes Mesodermal fibroblast-like cells that are present in adipose tissue Aka Adipose Stem Cells Can differentiate into a mature adipocyte In vivo signals are poorly defined Perhaps hormonal cues such as insulin
Macrophages and other immune cells reside in the adipose tissue
Macrophage: phagocytic cells that reside in most tissues and serve immune and non-immune functions that maintain tissue homeostasis Primary mediators of the innate immune response
Phagocytic cells: A cell, such as a white blood cell, that engulfs and absorbs waste material, harmful microorganisms, or other foreign bodies in the bloodstream and tissues.
Lymphocytes T-cells Regulatory T-cells (T-regs) New reports of T-cells in white adipose tissue In Obese persons, as T-regs ↓, inflammation in fat ↑
B-cells Antibodies
Neutophils, Natual Killer cells (NK), B and mast cells Also reported in adipose tissue May play important roles in adipose tissue function
Vasculature Potential expansion and involution of adipose tissue depots require the vascular bed to be able to grow or regress as appropriate
vasculature cont... Not a lot of blood vessels in white adipose tissue Adipogenesis Fat cell proliferation Angiogenesis Growth of blood vessels
Physiology of Adipose Tissue Energy storage Thermal/Mechanical insulation Metabolism of steroid hormones Endocrine functions
What is the Function of Fat? primary function of adipose tissue or body fat is energy storage. Our bodies make energy from the food we eat. But although our use of energy is constant, our food intake is not
Fat function cont... Adipose tissue triglycerides are derived from dietary lipids as well as from internal synthesis by the liver.
fat function cont. again Body stores energy in adipose tissue primarily in the chemical bonds of triglycerides.
Second function of fat A second function of fat is providing insulation that helps slow heat loss through the skin. Very low body fat percentage is associated with low body temperature which is not an optimal health condition.
Third function of fat Fat also provides protection or “padding” for vital organs and structures acting as a shock absorber in the body when we experience the physical impacts of life such as walking, running, sitting, and falling. in the palms, soles, and scalp.
Metabolism of Steroid Hormone The contribution of adipose tissue metabolism to steroid homeostasis can ↑ significantly when other sources of steroid hormones decrease (i.e. postmenopausal women) and when adipose tissue mass increases (e.g. morbid obesity).
Estrogen levels are two-fold higher in morbidly obese compared to lean men.
Sex Steroids Includes androgens, estrogens, and progesterones Est. and maintain secondary sexual characteristics and regulate reproductive capacity in mammals
Glucocorticoids Includes cortisol (or hydrocortisol) Regulate many aspects of metabolic function Insulin action, blood pressure, fat deposition
Endocrine Functions Lipostatic model, and Adipokines
Lipostatic model When body is low on adipose tissue, hormones signal brain to increase food intake and reduce energy expenditure Confirmed when Leptin and its receptor were found Adipose tissue = endocrine organ
Adipokines Signaling molecules that are released from adipose tissue
Endocrine Functions: Leptin Plays a significant role in the regulation of appetite and energy balance In obesity leptin levels are elevated in proportion to adiposity Leptin deficiency = morbid obesity, insulin resistance, impaired fertility, and reduced sympathetic nervous syst.
Leptin theories: Obese individuals are leptin-resistant Obese individuals have trouble interpreting the Liptin signal
Endocrine Functions: Adiponectin See low levels in obese individuals Reduced circulating adiponectin associated with: Reduced insulin sensitivity Increased rates of arthrosclerosis Impairment of immune function Levels increase after weight loss
Endocrine Functions: Resistin Inflammatory protein Produced by adipocytes in rodents; by macrophages in primates May play a role in development of obesity-induced insulin resistance.
Resitsin May have a larger role in insulin reistance that develops in inflammatory states (i.e. during an infection
Endocrine Functions: Tumor Necrosis factor-α Experimental data suggest high levels contribute to insulin resistance by: Impairs insulin signaling Increases serum free fatty acids
Endocrine Functions: Interleukin 6 (IL-6) A cytokine Its expression and serum concentration are raised with obesity and insulin resistance Is believed to decrease insulin-signaling, inhibit adipogenesis.
IL-6 levels in the CNS decline as fat mass increases in obese individuals Giving IL-6 to CNS increase energy expenditure and decreases body fat in rodents
Endocrine Functions: Plasminogen Activator Inhibitor (PAI-1) A protein An important inhibitor of fibrinolysis (the normal process of dissolving blood clots) Levels are elevated in obesity and insulin resistance
Pathophysiology of Adipose Tissue Lipodystrophy & Obesity
Lipodystrophy Impairment in adipose tissue accumulation Fat loss may vary from very small areas to near-complete absence of adipose tissue Uncommon in the general population
Lipodystrophy: Metabolic Consequences Hypertriglyceridemia Fatty liver Non-alcoholic fatty liver disease (NAFLD) Insulin resistance Diabetes Severity increase with extent of fat loss
Pathophysiology of Adipose Tissue: Obesity Histopathology of Adipose Tissue in Obesity and Altered adipose tissue physiology and metabolic consequences of obesity
By definition, obesity results from the intake of calories in excess of their expenditure
Weight loss occurs when energy intake is consistently less than energy expenditure
Weight gain occurs when energy intake consistently is greater than energy expenditure
weight stabilization occurs when energy intake consistently matches energy expenditure
Change in energy stores = Energy intake – Energy expenditure
The phrase “energy homeostasis” refers to the collection of biological phenomena that work to keep energy stores constant.
Energy homeostasis is coordinated by the central nervous system (CNS) that integrates signals generated in the periphery involved in hunger, feeding, satiety, absorbed nutrients and energy expenditure.
Why measure body weight for energy balance studies? Measuring body weight is an indirect method of monitoring the change in energy stores (i.e., body fat stores). Weight gain reflects an increase in stores and weight loss reflects a decrease. Weight stability implies that energy stores are unchanged
Short term feedback meal to meal -sight, smell, taste of food, biological signals.
long term feedback involves hormone/energy-sensing neurons in the hypothalamus that monitor signals generated by energy stores (i.e., depot fat) over extended periods of weeks or months.
long term feedback cont... The unused portion of ingested calories is processed and stored primarily as depot fat.
The integration of signals by these two brain regions (Arcuate nucleus (ARC) Paraventricular nucleus (PVN)) results in the generation of efferent (out to body) signals that control meal-taking (feeding) behavior.
Leptin is a peptide hormone that is manufactured and secreted by white adipose tissue that can cross the blood brain barrier to interact with neurons in the brain involved in appetite and body weight regulation
. Leptin is an important signal in the long-term component of appetite and body weight regulation because it reflects energy (i.e., fat) stores
Both Leptin and Insulin meet criteria for an adiposity feedback signal
Nutrient Signals Glucose Basic fuel of the body Fatty Acids (e.g. oleic acid) Amino Acids (e.g., leucine)
Signals Affect Feeding by: Increasing or decreasing hunger or motivation to eat Increasing or decreasing satiety Altering macronutrient (protein, fat or carbohydrate) appetite or intake Increasing the orosensory or rewarding (hedonic) properties of food
Signals Affect Feeding by cont... Increasing or decreasing meal size, meal frequency or meal duration Increasing or decreasing the between meal or inter-meal time interval Signaling the status of gastric distension or sense of fullness
Three non-homeostatic reward systems known to affect feeding are: The Dopamine system The Opioid system (-endorphin, enkephalins, and dynorphins) The Endocannabinoid system
Factors that may shift energy balance toward obesity development Genetic factors Developmental factors Environmental influences Hormone resistance
The Dopamine system dopamine functions as a neurotransmitter—a chemical released by nerve cells to send signals to other nerve cells.
The Opioid system An opioid is any psychoactive chemical that resembles morphine in its pharmacological effects. Opioids work by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract.
The Endocannabinoid system s a group of neuromodulatory lipids and their receptors that are involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory; it mediates the psychoactive effects of cannabis
Appetitive traits are individual characteristics associated with feeding behavior that influence food intake, energy balance and body weight.
In addition to meal frequency and quantity of food consumed, appetitive traits include hunger, satiety, food preferences, motivation to eat, eating rate and changes in eating rate during a meal.
Appetitive Traits Low responsiveness to internal satiety signals High responsiveness to external food cues (sight, smell or taste of food)
Appetitive Traits cont... Food preferences (e.g., preferences for energy dense or highly palatable foods or for fruits and vegetables, low fat foods, high fiber foods, etc.) High motivation or willingness to work to obtain preferred foods
More Appetitive Traits Greater sensitivity to the “reward” qualities of food Eating rate – Quantity of food consumed per unit time Absence of deceleration (or presence of acceleration) Quantity of food (and caloric beverages) consumed per week, per day.
Psychometric vs Behavioral Testing -Psychometric Testing Administration of validated questionnaire Less expensive Easier to administer Permit for larger samples Less objective Bias
Behavioral Testing Eating behavior is measured directly or through observation Expensive Time consuming Smaller sample sizes Reduced statistical power Reduced ability to differentiate between lean and obese subjects Vulnerable to extraneous factors
Three Factor Eating Questionnaire Cognitive Restrain Disinhibition Perceived Hunger
Dutch Eating Behavior Questionnaire Restrained eating Emotional eating External eating
Child Eating Behavior Questionnaire (CEBQ) Satiety responsiveness/slowness in eating Food responsiveness Enjoyment of food Fussiness Desire to drink Emotional under-eating Emotional overeating
Eating in Absence of Hunger Paradigm In the paradigm, the subject is first fed a meal and then asked to rate hunger. [Note: Only data collected from subjects who rate themselves as “not hungry” are analyzed further.]
Eating in Absence of Hunger Paradigm cont... The subjects are then exposed to other foods and their food intake in response to those foods is measured. Such studies are used to gain insight into appetitive traits such as high sensitivity to food cues or high sensitivity to reward.
Obese women have higher rates of: Hemorrhage.Maternal death.Postpartum weight retention.Birth defects.Suboptimal long-term health of the offspring. Spontaneous abortion.Fetal and infant death Preterm delivery.C-section delivery Excessive weight gain.Gestational diabetes.Pre-eclampsia.
The recommended weight gains are based on classifying the woman according to her prepregnancy BMI.If these goal weight gains are achieved, fat gain will be maximal in underweight women, less in normal weight and overweight women and lowest in obese women.
Only about 1/3 of women gain weight as recommended for their BMI group (most gain too much)
Pregnancy and Maternal Obesity Development-Obese= overweight= >29.0 >26.0-29.
The portion of women who were obese at entry to prenatal care (BMI >29) more than doubled between 1980 and 1999 from about 16% to about 37%
Percentage increases in prevalence were higher in women of the heaviest weights.
A more recent report 49% (or 42% if using old guidelines) with a BMI >25 is, overweight or obese
Concern about obesity developing or worsening after pregnancy. Studies show that women may permanently add substantial weight during/after pregnancy Lowering recommendations will not prevent continued postpartum gain
More concerns about obesity developing or worsening after pregnancy. Studies indicate that gains of a few kg of fat in early pregnancy could have effect on total fat gain
Up to approx. 20% of women gain extra 5 kg or more than 6-18 months postpartum compared to pre-pregnancy weight
Reasons a Women May Weight More One Year Postpartum. May not have lost all of the weight she gained during pregnancy.May have gained weight after losing all of the weight gained during pregnancy.Her pre-pregnancy weight may have been underestimated.