Physiology of Obesity- Quiz 1
Abdominal obesity is risky. Why? What factors contribute to increase and loss of abdominal fat?
- Abdominal obesity promotes dislipidemia Healthy lipid profile: normal triglycerides, normal LDL cholesterol (want larger molecules rather than smaller molecules of this "bad cholesterol"), & normal HDL cholesterol (want large HDL molecules, this is "good cholesterol") Obese lipid profile: high triglycerides, normal LDL cholesterol but the molecules are small instead of large, & low HDL cholesterol and the molecules are small instead of large -Factors that contribute to abdominal fat: Chronic stress or maladaptation to stress Elevated cortisol (Cushing's syndrome) Low subcutaneous fat or lipodystrophy Genetic predisposition Smoking Diet: trans fats, fructose drinks -How to lose abdominal fat General weight loss - this is the first to go Exercise (prevents deposition in the abdomen) Diet - high fiber, low or no trans fats Probably reducing stress
What controls hunger and what role does ghrelin play?
- Leptin decreases hunger (satiety, increases drive to move and decreases drive to eat when leptin levels are high) and ghrelin increases hunger (increases drive to eat & decreases drive to move) - Ghrelin increases hunger in a short term manner Asprosin is released from fat cells, thought to be the counterpart to leptin - Asprosin is released during fasting & stimulates appetite (while leptin decreases appetite) - Mechanical and chemical satiety signals in stomach Stomach distention (mechanical) & nutrient induced release of CCK both will stimulate vagus nerve → suppresses appetite -Incretins: PYY, OXM, GLP-1, & GIP all stimulate insulin release from pancreas, stimulate hypothalamus → promotes satiety -These incretins also activate dorsal vagal complex (DVC) which suppresses appetite Lack of available nutrients stimulates appetite
What do the single genetic mutations in humans (which all cause severe obesity) tell us about body weight control in humans (i.e., what pathway are they part of)?
- Leptin pathway, leptin plays huge role in weight regulation If a person is leptin deficient due to a genetic mutation, weight gain occurs & obesity results (can be solved with leptin injections) - Can also be deficient in the LepR receptor (no cure or treatment), obesity also results with this condition - Melanocortin 4 receptor (MC4R)- MOST COMMON MUTATION - POMC (the precursor to alpha MSH that affects the pathway of leptin) - SIM1 -part of MC4R pathway - KSR2 - only one not part of leptin pathway. causes hyperphagia (extreme hunger)
What do we know about the roles of leptin, ghrelin, and asprosin in long-term body weight control?
- Leptin: Leptin is most important hormone known to have long term impact on body fat/ weight Low leptin signal that fat cell mass is too low and signals to the hypothalamus to increase our drive to eat and decrease our motivation to move High leptin decreases drive to eat and increases motivation to move when fat mass is expanded Leptin response is impaired with obesity (A high level of leptin does not effectively decrease appetite and increase energy expenditure call leptin resistance) Leptin resistance - this is why you can't inject obese people with leptin to help with weight loss Leptin is assisted by insulin!!! It sensitizes the hypothalamus to leptin & allows it to decrease appetite, giving insulin a role in long-term appetite control - Ghrelin plays a role in appetite and body weight Released by stomach and GI tract (before meals, circadian) Increases appetite and decreases energy expenditure (greater effect in obese) Suppresses fat utilization and promotes fat storage Stimulates growth hormone release from pituitary → increases lean body mass and increases blood glucose (stress hormone) - Asprosin: released from adipose tissue → acts on hypothalamus to stimulate appetite
What is the link between adenovirus and obesity?
- Obesity began to skyrocket in the 80s when human adenovirus was first discovered... the analogs of adenovirus cause obesity in chicken, mice, & primates - Causes increased insulin sensitivity, increased glucose intake, decreased leptin in animals (associated with better glycemic control in humans)
What effect does high chronic cortisol have on body fat distribution?
- Psychological theory: chronic stress → preferential fat storage in the abdomen → reduction of chronic stress (propagates preferential abdominal fat storage as a response to chronic stress) Acute stressors provoke transient increases in HPA activity that are self-limited because of rapid feedback effects of glucocorticoids on the motor output of the axis. Additionally, acute stressors alter behavior and may, through elevated glucocorticoids, enhance the motivation to eat high-sweet, fatty foods (left). With a chronic stressor, the elevated glucocorticoid signal acts positively on brain to promote further activation of the chronic stress response system. Glucocorticoids and insulin further augment the drive for and hedonic response to high sweet and fatty foods (middle). When a combination of elevated glucocorticoids and insulin has acted to increase intraabdominal caloric storage, an unidentified signal from these stores acts on brain to reduce the overall level of activity of the chronic stress response network (right).
how might stress promote obesity?
- Sleep deprivation → increased cortisol, sympathetic nervous system activity → increased ghrelin and decreased leptin - Odds ratio of obesity based on average sleep duration increases when amount of sleep decreases Chronic stress of maladaptation to stress → theory: when stress stimulates fat storage in the abdomen, stress levels are reduced (psychological propagation of fat storage) - Cushing's syndrome: chronically elevated cortisol; more abdominal fat, limb thinning, moon face, buffalo hump - States with reduce sleeping times coincide with obesity - Sleep deprivation decreases leptin (satiety) and increases ghrelin (hunger) - Increases cortisol, insulin → inc. ghrelin and dec. leptin
Where is brown adipose tissue (BAT) located? What factors stimulate it? What factors are associated with more or less BAT or beige adipose tissue? Why is BAT considered a promising therapeutic target?
- Where is BAT located ---> BAT is in babies throughout the torso and is located under the clavicle in adults, more BAT in women and younger leaner adults - What stimulates it ---> BAT is primarily stimulated by the sympathetic nervous system in response to cold temperatures Regulates brain temperature Stimulants of BAT Drugs, irisin, menthol, capsaicin -What factors are associated with more or less BAT or beige adipose tissue? --> Norepinephrine is stimulated by the cold and can beige white adipose -->UCP1 expressed exclusively in BAT -Why is BAT considered a promising therapeutic target? --> More studies indicate anti-obesity effects of brown fat Loss of UCP1 in mice → obesity in thermoneutral temperatures Activate or transplant brown fat → loss of white adipose, resistance to diet-induced obesity, increased insulin sensitivity Some obesity and insulin resistance prone mice → less brown adipogenic potential Having brown adipose is beneficial for metabolic health. When fully activated, it could account for ~20% of basal metabolic rate Effectiveness of boosting brown fat is unproven Brown fat stimulation may increase appetite to compensate for energy utilization - Negative side effects might include: Heat intolerance Increased cardiovascular disease events Link between cold weather and CVD Utilizes fat and some carbs Instead of ATP it generates heat- -It contains many mitochondria and uncoupling protein 1 (UCP1). Present in babies. More adipose in women and younger, leaner adults. Found around the neck, kidneys, adrenal glands, heart, and chest. Produces heat instead of ATP and utilizes fat and some carbs. It is primarily stimulated by the sympathetic nervous system in response to cold. White to Brown Fat Phenotypic Switch Induced by Genetic and Environmental Activation of a Hypothalamic-Adipocyte Axis. Brown adipose tissue has common lineage with muscle cells but it can also arise from white adipose (beige fat). When fully activated, it could account for ~20% of basal metabolic rate.
features of FTO gene variant
- fat mass and obesity associated protein; variant w greatest effect on BMI and associated w obesity, but only homozygous individuals have a significant increase in BMI -Cluster of 10 nucleotides SNPs (AA genotype) -Increases expression of IRX3 and IRX5 in white fat -With AA alleles: Secrete more ghrelin Greater food consumption, increased fat intake, impaired satiety (always hungry) More white fat cells and less beige fat cells Can prevent weight gain with exercise -Individuals with AA have higher BMI starting in childhood
Diagnostic criteria for metabolic syndrome
- impaired glucose regulation/insulin resistance : fasting plasma glucose > 110 mg/dl - abdominal obesity: waist circumference in men > 40 inch or for women > 35 inch - high blood pressure (greater than 130/85) - hypertriglyceridemia: > 150 mg/dl - low HDL cholesterol: less than 40 mg/dl in men and 50mg/dl in women
Relationship between fitness and obesity and which affect disease risk more?
- inactivity is linked to obesity - in WOMEN: fitness inversely related to BMI, low fitness correlates to metabolic syndrome, - in MEN: fitness correlated w reduced mortality risk - cardiovascular respiratory fitness decreases mortality risk
Stats/Trends in Obesity and Exercise in the US
- obesity increases mortality - risk factor for major causes of death - increasing in US adults - average BMI slightly increased over decades - from 2017-20: 42% adults obese and 20% children
What are the potential causes of obesity (both genetic and environmental)?
- single gene mutations - susceptibility genes - chronic stress (elevated cortisol) - inactivity/high fat, high sugar and low nutrient diet - microbes (virus and bacteria) - obesogens
What activates AMPK? What are the effects of activating AMPK?
-AMPK is a cellular energy sensor: activated my lower E in the cell (ex: during exercise when energy is rapidly consumed) and when activated it upregulates metabolic capacity of the cell which improves mitochondrial function -AMPK activators --> Adipocytokines: adiponectin, apelin, leptin --> Exercise, some diabetes drugs and AICAR - Activating AMPK in muscle: --->Mitochondrial biogenesis (increased number and size of mitochondria) --->Mitophagy (eliminate dysfunctional mitochondria) --> Increase beta oxidation ---> Increase glucose uptake Net effect: increase insulin sensitivity o Increases glucose uptake in muscle independent of insulin receptor o AMPK pathway promotes better insulin signaling by stimulating insulin pathway -Apelin also activates AMPK by enhancing glucose uptake (by increasing GLUT4 transporter translocation to the membrane which increases function of mitochondria so they can more readily oxidize fats)
What categories of factors are secreted from adipose tissue?
-Adipokines- small peptide molecules released from adipocytes specifically leptin, adiponectin, visfatin/NAMPT/PBEF, & apelin Apelin: improves glucose metabolism - Resistin: correlates systemic inflammation and insulin resistance - Omentin: marker of visceral fat mass, promotes endothelial function - Adiponectin: positively affects CV system, activates AMPK → mitochondrial biogenesis (producing more and bigger mitochondria → more energy produced) and mitophagy (removing damaged ones, which pump out oxidants that can damage cell), adiponectin also enhances lipid use ability -Cytokines/cytokine-like proteins -Proteins of fibrinolytic system- removes fibrin from vascular system to prevent clots from occluding vessels -Complement/complement-related proteins -miRNAs -Enzymes -Lipid transport molecules -Proteins of RAS system esp. angiotensin -Endocannabinoids & other lipids... esp. Free fatty acids for mobilization
How effective is each treatment for obesity? What are the mechanisms of action of the obesity drugs?
-Calorie restriction has poor long-term success -Exercise boosts appetite, so it's minimally effective for short term WL, but good for maintenance -Drugs have some effect but lots of side effects 5% of weight lost in over 50% of patients is the standard for FDA approval -Orlistat (Xenical) Blocks fat absorption in intestine gastro-intestinal side effects -Qsymia Anticonvulsant (topiramate) + amphetamine (phenteramine) Causes about 13-15% weight loss (very effective) Disturbing neurological side effects Weight comes back on after stopping - Contrave Antidepressant (bupropion) + opioid receptor antagonist (naltrexone) 5% weight loss in half of patients Suicide risk -Tirzepatide (FDA approved in May 2022) GLP-1 and GIP agonist: acts like incretins released from the intestine... acts on pancreas to release insulin Digestive tract side effects are common -Metformin → improves insulin resistance and can decrease weight Diabetes drug GLP-1 receptor agonists (eg liraglutide, exenatide) → increases satiety, FDA approved as an obesity drug in 2020 -Pramlintide → an amylin analog, increases satiety, injected, causes nausea -Bariatric surgery - effective but very risky Digestive tract is altered in a permanent manner -Composition of the diet - minimal evidence so far
What is irisin and what are its effects in mice and humans?
-Released from exercised muscle, inducing adipose browning -Increase in plasma irisin after 8 week exercise training (n=8) in humans -Irisin's role in humans is controversial -It seems to increase acutely in blood after intense exercise -Unclear whether it increases with exercise training (problems with measurement) -Unclear whether exercise training increases brown fat
Benefits of exercise
-regular exercise PREVENTS: coronary heart disease, death, type2 diabetes, colon cancer, disability + reduced phys function -regular exercise LIKELY PREVENTS: breast cancer, obesity, stroke, decline in immune function - regular exercise MIGHT prevent: depression, lung cancer, gall-bladder disease
How might epigenetics contribute to obesity?
2 epigenetic changes: methylation of cytosine and modifications of histones -Methylation of cytosine: Add methyl group which can activate or repress genes -Modifying histones: histones are made of 8 protein subunits; amino acids can be modified by adding acetyl groups, or phosphorylation) - Histones unwound (acetylation and phosphorylation both can) → opens gene for transcription - Wound tightly (mostly methylation) → genes can't be transcribed -Epigenetic changes are environmentally induced and are heritable for at least 2 generations - Exercise in pregnant mothers protects baby against obesity - Environmental toxins like BPA can affect epigenetics
With regard to the 5 specific adipocytokines we discussed: How do they change with obesity? What actions do they have in the body? Are the actions beneficial or pathological?
Adipocytokines change with adipose expansion, which promotes inflammation o Weight loss but not necessarily exercise improves adipocytokines - 4 beneficial o Leptin § Released in proportion to fat mass § Decreases appetite and increases energy expenditure § Activates hypothalamic POMC/CART neurons (satiety pathway) § Inhibits hypothalamic NPY/AgRP neurons (hunger pathway) o Adiponectin: secretion decreases (very bad bc this is an anti-inflammatory molecule)... adiponectin also is a marker of insulin sensitivity & AT function. Adiponectin is the only hormone we discussed whose levels DECREASE (all of the rest increase) o Apelin: Apelin increases, & apelin increases insulin sensitivity o Visfatin/nampt: PBEF/visfatin increases (PBEF is regarded as pro-inflammatory, visfatin is linked to several inflammatory conditions & CVD, but stimulates insulin release & enhances fat storage - 1 detrimental o Visfastin:
What changes occur in white adipose tissue with obesity and metabolic syndrome? How does this affect adipocytokine release?
Adiponectin secretion decreases (very bad bc this is an anti-inflammatory molecule)... adiponectin also is a marker of insulin sensitivity & AT function Adiponectin is the only hormone we discussed whose levels DECREASE (all of the rest increase) PBEF/visfatin increases (PBEF is regarded as pro-inflammatory, visfatin is linked to several inflammatory conditions & CVD, but stimulates insulin release & enhances fat storage) Leptin increases (but sensitivity is reduced w/ obesity)... leptin decreases appetite, increases energy expenditure, increases insulin sensitivity Resistin increases, functions to decrease insulin sensitivity Apelin increases, & apelin increases insulin sensitivity NOT ADIPOSE TISSUE BUT STOMACH TISSUE: Ghrelin secretion decreases, function of ghrelin is to increase appetite (does not make that much sense) Leptin & resistin are considered pro-inflammatory adipokines & their secretion increases w/ obesity, while adiponectin is considered anti-inflammatory but decreases secretion w/ obesity In metabolic syndrome, leptin increases and adiponectin decreases
Paper 1: Weight-Reducing Effects of the Plasma Protein Encoded by the obese Gene
Background -The friedman lab identified (cloned) the genes that causes extreme obesity and diabetes in obese (ob) mice -The receptor for this protein was identified (cloned) in diabetic (db/db) mice in 1995 -Ob mutation results from one wrong base on the DNA -Ob is missing hormone and db is missing receptor Hypothesis: Injection of the OB protein into ob/ob mice (deficient in OB protein) will result in decreased food intake and weight loss Parabiotic union is when the skin/muscle of two animals are sutured together so that they share a blood supply. When ob mice (yellow) were joined with wild-type mice (gray), the Ob mice lost weight, suggested that the wild-type mouse transferred a blood factor to the ob mice who were missing it. When db mice (red) were joined with wild-type mice, they did not lose weight, suggesting that the db gene is not a blood factor. When ob and db mice were joined, the ob mice lost weight indicating that the db mice had the blood factor but could not respond to it. This suggests that db mice are missing the receptor for the factor. Conclusion -OB protein injection in mice -Decrease food intake -Decrease body mass -Increase energy expenditure db/db mice don't respond to OB protein Suggests defective receptor (or OB signaling) Named this protein Leptin for leptos (meaning thin)
Paper 2: Asprosin is a centrally acting orexigenic hormone
Background: Asprosin was Discovered in 2016 as a Fat Cell Hormone Asprosin ↑'s with Fasting and ↓'s with Feeding Asprosin ↑'s Blood Glucose and Insulin Asprosin ↑'s Liver Production of Glucose Humans missing FBN1 have neonatal progeroid syndrome (NPS) and are severely lean (lipodystrophy). Hypothesis: Asprosin is a hunger hormone Conclusion: Aprosoin promotes hunger, fat mass and lean mass in mice and likely humans Asprosin directly activates AgRP neurons in hypothalamus (hunger pathway) in mice Suppressing asprosin prevents obesity in leptin deficient mice and high fat diet fed mice Significance Asprosin may be the direct adipogenic counterpart to leptin Update: Anti-asprosin treatment (mAb's) improves diet-induced obesity and diabetes in mice
Paper 3: An exercise-inducible metabolite that suppresses feeding and obesity
Background: Exercise effects many systems and promotes health Many exerkines effect cardiometabolic health Hypothesis: Of the exerkines released after exercise, which change the most? What is their function? Appetite decreases after acute exercise: could be due to decrease in ghrelin, increase in GLP-1, increase in PYY Conclusion Lac-Phe is the exercise induced serum metabolite that increases in most mice Produced by CNDP2 (high expression in immune cells and epithelial cells (from rate limiting substrate), need to have lactate as a precursor Daily Lac-Phe injection in mice decreases food intake, weight gain and insulin response in high fat diet mice, with no change in metabolism CNDP2-KO mice attenuates reducing effect of exercise Acute exercise increases Lac-Phe in humans and horses Humans: sprint > resistance > endurance (correlates with lactate) Significance Lac-phe is a potentially physiological therapeutic for obesity
Paper 5: Tirzepatide for the Treatment of Obesity
Background: GIP and GLP-1 are incretins and satiety peptides Hypotheses Paper 5a: The GIP/ GLP-1 dual agonist tirzepatide will promote weight loss in those with obesity but did not test diabetics Paper 5b: It will effectively decrease liver and abdominal fat in diabetics Paper 5c: it will improve pancreatic beta cell function and insulin sensitivity in diabetics Methods: terzepatide injections, paper 5c has a different method Conclusions: Paper A: Over 80% of nondiabetic obese subjects lost 16-21% more percent of weight than placebo Paper B: Significant decrease in liver fat (greater than control) & visceral fat (increase in liver fat occurred in control) Fatty liver is big problem w/ diabetics esp type 2, reduction of liver fat is critical in addition to overall weight loss Paper C: Significant increase in glucose disposal rate, insulin secretion, and insulin sensitivity and significant decrease in glucagon secretion Good diabetes drug and weight loss is a positive side effect All mechanisms that control glucose improved Significance Drug was approved by FDA for weight loss in may 2022 There were deaths If it wasn't for covid there may have been no deaths
Paper 4: Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity
Background: Impaired MC4R receptor leads to obesity MC4R activated by alpha MSH MC4R activates adenylyl cyclase and ERK 1/2,and β-arrestin binds to promote internalization Hypothesis: naturally occurring human genetic variants of MC4R will provide information about the receptor's function and guide drug design for activating the receptor Approach: Screen 0.5 million people (age 40-69) for MC4R nonsynonymous mutations → found 61 Screen variants for ability to increase cAMP and bind beta-arrestin (cell culture) Determine how receptor function correlates with BMI Conclusions -Gain of function MC4R is associated with a lean phenotype, lower diabetes and CVD -The most common gain of function mutation causes -Increased B-arrestin recruitment, but more receptors at membrane → increased MC4R signaling Significance Supports the dominance of the leptin/ alpha MSH/MC4R pathway in body fat regulation in humans Identifies a naturally occurring mutation (in either 6 or 16% of european ancestry individuals) that enhances this pathway May assist in development of targeted/ personalized obesity treatments
Why might bariatric surgery be an effective treatment for weight loss and for diabetes correction in particular?
Changing GI structure - Gastric sleeve cuts out part of stomach, roux en Y diverts food right into intestines, bypasses stomach - Lap band closes off stomach - Bypass is very effective (and over 80% diabetes correction immediately) - Nutrient dump right into intestine → GLP1 response (satiety hormone) lowers appetite, improve glucose control
Very few people are successful at long-term weight loss. What is characteristic about them?
Exercise at least 1hr/ day Eat breakfast everyday Eat low-fat (~24%), high fiber low calorie diet Consistent eating pattern Specific personality type - regimented, controlled, methodical, punctual, neat
Does changing macronutrient composition of the diet affect weight loss? If so, how?
Extreme changes in macronutrients are hard to sustain Greatest weight loss with Atkins: low CHO, but all groups (diets) lost the same amount over 2 years. -extreme changes in macronutrients is hard to sustain. study groups always drifted back to normal macronutrient proportion diet (half carbs, 30% fat, 20% protein) within a few months. -effectiveness of diet depends on insulin resistance status. Insulin resistance subjects lost more weight with low CHO than low fat. -Study from Europe found: high Protein/ low Glycemic index led to continuous weight loss
What are the possible causes of leptin resistance?
High chronic leptin → leptin resistance - Built in mechanism - Sequestration in the blood - CRP (inflammatory factor) prevents leptin from crossing BBB - Impaired leptin transport across capillary wall - Needs endothelial cells since they have functioning leptin receptor - Within neurons: attenuation/decreasing of receptor signaling through SOCS3 and one other factor that's transcribed in response to leptin signaling (PTP1B) - So impaired leptin receptor signaling in hypothalamus - Inhibition of leptin receptor through actions of SOCS3 or PTP1B from neuron, OR PTP1B from adipose tissue - SOCS - Voles have increased SOCS3 during period time where they have to gain weight - Theorized that what allows them to begin to gain weight is functional leptin resistance - Pregnancy → increased leptin and increased leptin resistance (through increased SOCS3) - Prolactin goes up with pregnancy steadily, acts through prolactin receptor → promotes SOCS3 production → impairs leptin signaling - In rodents: pathological- When put on HFD → stimulates inflammatory pathway through inflammatory receptor → produces inflammatory signaling in cells → increases SOCS3 - At least under normal physiological conditions, hypothesized that leptin resistance has important function to regulate increase in body fat set-point - Potential causes for leptin resistance in humans - 1. Prolactin (proposed mechanism in rodents) - Could be the case in pregnant women - 2. HFD - great evidence for that in animals - 3. High sugar or high fructose diet - 4. Overall general inflammation
How might consumption of high-fat and or high fructose foods promote obesity?
High fat diet promotes greater calorie consumption - Glucose and fructose promote weight gain, but only fructose increases visceral fat - Fructose consumption correlates with rise in obesity - increases palatability of food, fails to acutely stimulate insulin and leptin after feeding - Glucose does this; promotes more satiety through leptin signaling - Also fails to attenuate (reduce) ghrelin secretion after feeding - glucose and AA's suppress ghrelin/reduce appetite) - High fructose induces leptin resistance in rats (in rats with high fructose diet, leptin injection doesn't decrease food intake as well - pSTAT3 (marker of leptin signaling) is reduced in high fructose rats - Impaired response to leptin w/o leptin receptor impairment - Fructose intake → high visceral adiposity and metS (correlate) - Short-term: inc. weight, liver fat, triglycerides (inc. triglycerides can promote leptin resistance) - High fat diet might cause leptin resistance - High fat diet → promotes higher calorie intake - Increase in dietary fat percentage → increase in kilocalories consumed- Glucose and fructose promote weight gain, but only fructose increases visceral fat - Overconsumption of carbs and simple sugars could contribute - Study in humans: sugar-sweetened beverage with glucose vs fructose - Ate more total calories, pretty much everyone gained weight same amount - Glucose group: gained mostly subcutaneous adipose tissue (under skin) - Fructose group: gained more visceral fat
How might gut bacteria be linked to obesity?
Human Microbiome Project (NIH) ○ 10x more microbes are in body than human cells ○ Some involved in food metabolism, some prime immune system (baby born → gut is sterile → exposure to microbes helps develop immunity), some produce vitamins ○ High volume of microbes in colon - Bacteria is also similar in related individuals ● Gut bacteria differ between lean and obese ○ Obesity → more firmicutes/bacteroidetes ○ Humans with less microbiome diversity → higher adiposity, insulin resistance, dyslipidemia, inflammation (found from stool samples) ○ Microbiome changes with pregnancy, looks a lot like metabolic syndrome ● Bacteria from obese gut promotes obesity ○ 2 groups lean mice: transplant one group with Ob/Ob microbiome → weight increase by 40% Ob/Ob mice extracted more calories from their food and transplant of their fecal bacteria promotes obesity
What is a commonly measured gene to indicate leptin signaling (i.e., its expression increases)?
Intracellular leptin signaling --> Activates STAT 5 and STAT 3 (marker for leptin receptor activation) SOCS3 - inhibits receptor, potential site for leptin resistance Leptin injection increases pSTAT3 (marker of leptin receptor signaling). This is depressed with 60% fructose diet
What areas of brain are affected by factors contributing to hunger? What are cell signaling pathways in the brain? how does leptin/ghrelin/satiety signals affect these pathways
Leptin released into bloodstream → crosses BBB to act on cells in the arcuate nucleus (AN), where there are two main cell types: POMC/CART and NPY/AgRP (leptin acts at both) - POMC = full length precursor protein, cell synthesizes it then cuts into various NTs (acts on leptin receptor in BB barrier) - Primary satiety pathway: POMC/CART neurons stimulated by leptin receptors → stimulate release of hormone alpha-MSH → they travel to PVN (post ventriculate nucleus) and bind to MC4 receptors (mutated MC4 is the most common genetic leptin pathway defect) → stimulates decrease in appetite, increase in energy expenditure (does through the SNS) - Hunger pathway: Ghrelin and asprosin act on NPY/AgRP neurons to release NPY hormone → act on PVN neurons to inc. appetite and dec. energy expenditure - NPY/AgRP releases AgRP to block alpha-MSH, inhibiting POMC/CART - Leptin attempts to block ghrelin by blocking NPY/AgRP (leptin overtakes if they are both present at once) - As long as leptin is around → NPY/AgRP inhibited, satiety receptor activated - Short term satiety factors (primarily gut/pancreas factors) block NPY/AgRP neurons - Satiety is blocked by hunger signals (AgRP release blocks alpha MSH/blocks MC4 binding/blocks satiety) → leptin overtakes, causes hunger again
What are obesogens and what is thought to be the common way in which they promote obesity?
Obesogen = chemical in environment that could be promoting obesity ● Endocrine disruptors → interfere with or take place of normal hormones → disrupts normal biology ○ BPA → causes obesity in young animals ○ Parabens ● Obesogens are endocrine disruptors ○ Increase number and size of fat cells; alter endocrine regulation of adipose tissue development; alter hormones; alter basal metabolic rate; alter energy balance in favor of storing over utilizing calories; alter insulin sensitivity -Exposure to DES in neonatal periods leads to obesity in mice
What do human overfeeding studies tell us about the physiological characteristics that confer susceptibility to weight gain with overfeeding?
Reveal genetic variation in weight gain with chronic excess calories Weight gain, fat gain, less mass gain are similar within twin pairs but vary greatly among pairs Conclusion - metabolic rate increases to prevent weight gain, but is highly variable and based on genetics Baseline physiological characteristics that are associated with greatest fat gain with overfeeding: Low FFM, low muscle oxidative potential, low VO2max, low androgenicity, high leptin levels, low cortisol, low DHEA, TSH response to TRH, high estrogenicity, low postprandial energy expenditure, large abdominal fat cells Overfeeding studies indicate: Large differences in amount of weight gained (and partition of fat and lean mass) with overfeeding that correlate with oxidative capacity (VO2 peak) and hormone levels (particularly androgens) VO2 Peak = Max amount of oxygen you can utilize during max aerobic exercise, depends on ability to deliver oxygen to working tissues, depends on health of heart and blood vessels, ability to pick up oxygen, ability of muscle to utilize oxygen Genetic predisposition + obesogenic environment = high obesity prevalence Ex. Pima Indians
How are the SOCS proteins involved in leptin resistance?
SOCS induces leptin resistance Voles have seasonal regulated increases in body weight Put on fat → increases leptin → increases leptin resistance (increased SOCS) Pregnancy → increases leptin and resistance to leptin increases (increased SOCS) Leptin resistance may regulate an increase in body fat set-point SOCS inhibits the transcription of STAT3, which marks the leptin receptor for activation. In other words, SOCS inhibits the signal transduction of cytokines in our body, including leptin, thus inducing leptin resistance
What is known about risk (susceptibility) genes for obesity?
Susceptibility genes: hundreds of genes identified that affect energy intake and utilization - its very hereditary! - Most powerful human risk variant: Fto gene - Obesity risk allele on human chromosome 16 (10 SNPs with AA genotype) - 1 copy → +0.27 BMI (45% of population) - 2 copies → +0.8 BMI (16% of population) - Inc. expression of IRX3 and IRX5 in white fat - More ghrelin, more food intake/less satiety, more white fat and less beige, can prevent weight gain with exercise.
What gene is the key marker for brown fat? What types of stimuli might cause "browning" of white adipose?
UCP1 is expressed exclusively in brown adipose and results in heat generation instead of ATP synthesis in mitochondria An enriched environment stimulates brown fat activity and conversion of white to beige fat in mice - What causes browning Irisin ! Possibly through exercise
Why is it difficult to lose weight?
With a constant energy deficit (25% less calories per day), hunger increases progressively and resting energy expenditure decreases. This makes it progressively more difficult to lose weight and to maintain the weight loss
How might fructose consumption cause weight gain and what do we know about its effects on leptin sensitivity?
i) The rise in fructose consumption correlates with the rise in obesity ii) How might high fructose cause weight gain - Increases palatability of food - Fails to acutely stimulate insulin and leptin after feeding - Fails to attenuate ghrelin secretion after feeding - Chronic fructose feeding → associated with increased leptin and elevated triglycerides iii)High fructose diet induces leptin resistance in rats - Leptin injection decreases food intake in rats consuming a normal diet, but not rats consuming a 60% fructose diet - Leptin injection increases pSTAT3 (marker of leptin receptor signaling). This is depressed with 60% fructose diet iv) High fructose diet increases food intake and weight gain with a high fat diet in rats v) Can high fructose cause obesity in humans 1.Epidemiology: high fructose intake correlates with a. increase visceral adiposity b. Metabolic syndrome 2. Short-term fructose feeding - Increased weight - Increased liver fat - Increased triglycerides → may cause leptin resistance Overall: unclear whether high fructose causes obesity in humans
Are abdominal fat (waist circumference) recommendations the same for all ethnicities? If not, which groups have lower targets?
no! Lower for Asian, Middle Eastern, African, and Hispanic
Does exercise training alter adipocytokines?
no, just weight loss
What hormones and factors control appetite and where/when are they released and where do they act?
short term satiety signals: nerves in stomach, hormones released from intestine, pancreas and nutrients sensed by brain long term satiety signal: leptin Adipokines (leptin), ghrelin, and asprosin, and release nutrients control appetite - leptin: released from adipose tissue and stimulates hypothalamus to decrease appetite. long term satiety signal - ghrelin: released from stomach/intestines. high before a meal, low after -asprosin: released from adipose tissue and stimulates hypothalamus to stimulate hunger. -nutrients: released from enteroendocrine cells in stomach and act as satiety signals. Nutrient release causes CCK to release which stimulates vagus nerve to suppress appetite in brain stem. -incretins (PYY/OXM/GLP-1/GIP) act on hypothalamus to promote satiety and they stimulate the pancreas via the release of insulin from pancreas -insulin released from pancreas also signals satiety and stimulates the hypothalamus -pancreas releases a polypeptide and amylin which stimulate brainstem to signal satiety
