Complementary Final Flashcards
Male vs Female body weight percentages
Male - more Muscle/Bone
Female - more essential/nonessential fat
Male vs Female LBM
Male Lean Body mass - 3%
Female Lean body mass - 12%
What has happened to worldwide obesity since 1980
It has doubled
What is the fundamental cause of obesity/overweight individuals?
An energy imbalance between calories consumed and calories expended.
An acute or subacute or chronic state of nutrition in which varying degrees of overnutrition or undernutrition with or without inflammation activity have led to a change in body composition an diminished function.
Malnutrition
What types of cancer/disease are common due to malnutrition?
GI cancer Head/Neck cancer Lunge Cancer Pancreatic cancer Chronic Obstructive pulmonary disease Cerebrovascular Accident
How does catabolic stress shift metabolic demand?
Acute phase response favors an increase in resting energy expenditure and promotes a catabolic state.
What does malnourished inflammation promote?
Muscle Catabolism Inhibition of protein synthesis and repair Hyperglycemia Decreased visceral proteins Edema Anorexia Deconditioning or Sarcopenia
What is Sarcopenic Obesity?
Obesity that occurs when there is an increase in fat mass and a decrease in lean muscle mass.
What is Starvation-related Malnutrition?
Chronic starvation w/o inflammation
- anything that limits access to food;
Anorexia nervosa
Marasmus
What is Chronic disease-related malnutrition?
Malnutrition where inflammation is chronic and of mild to moderate degree, common in Organ failure, Pancreatic cancer, RA and Sarcopenic obesity.
What is Acute disease or injury related malnutrition?
malnutrition where inflammation is acute and of severe degree
e.g. Infection, burns, trauma, or closed head injury
What is Obesity?
a complex multifactorial chronic disease that develops from an interaction of genotype and the environment. It involves the integration of social, behavioral cultural, physiological, metabolic and genetic factors.
What has happened to overweight and obesity rates since 1980? Childhood obesity?
everythings gone up. whoa
Where else in the world have obesity rates increased?
literally everywhere
What happened to obesity when dietary fat is reduced as a percentage of Kcals?
Still an increase, as people added sugar to make up for loss of fat.
What does Diet mean according to its original translation?
Manner of Living
How might you calculate BMI?
weight (kg) / (height (m)^2
or
(Weight (lbs) X 703) / height (in)^2
What are the assessments of risk for co-morbidities due to Obesity?
- BMI +25
- Waist circumference
- Men : 40”
- Women: 35” - Weight gain since age 18
- Level of Fitness
- Both Aerobically and Anaerobically required
How many deaths a year are due to obesity?
~300,000
*2nd cause of preventable mortality behind smoking
What does NHLBI expert Panel attribute to the cause of obesity?
60% Environmental
40% genetic
All-cause mortality is lowest within what BMI?
20-25
With a 10% increase in weight, what would be the effect on FBG? systolic BP?
FBG - 2-3mg/DL
BP - 6-7mmHg
What is Metabolic Syndrome?
Clustering of metabolic abnormalities, including resistance to insulin-stimulated glucose uptake, hyperglycemia, hyperinsulinemia, Increase in triglycerides and decreased HDL-Cholesterol
What factors may contribute to a person’s overweight/obesity?
Genetic/Hereditary Socio-Economic Status Race/Ethnicity Dec. Physical Activity Diet Early Puberty
What five factors establish Metabolic Syndrome?
Chronic Inflammation (increased C-reactive protein)
Hypertension
Visceral Obesity
Dyslipidemia (inc Tryglycerides and decreased HDL)
Glucose Introlerance
What specific diseases may Metabolic Syndrome lead to?
Type II Diabetes
CVD
Cancer
What other Conditions are often associated with Obesity due to Relative risk factor?
Diabetes type II Gall Bladder disease Sleep Apnea Hypertension Osteoarthritis Gout Coronary Heart Disease Stroke
What type of upper body fat distribution increases the risk of metabolic complications?
Central or Visceral Adiposity
What risk is there for having lower body subcutaneous adiposity relative to central/visceral adiposity?
Minimal Risk w/ lower body obesity.
How does Adipose tissue work as an Endocrine Organ?
Increases Lipoprotein Lipase Increases Leptin Increases IL-6 Increases PAI-1 Increases Adipsin Increases Serum Free Fatty Acids Increases Angiotensinogen Increases Lactate
How can an increase in triglycerides lead to Hyperglycemia?
Lipoprotein Lipase releases TG from visceral adipose, leads to hypertriglyceridemia, which acts in the liver to lower HDL and increase LDL, causing metabolic insulin resistance and eventually Hyperglycemia.
What common Hormonal abnormalities are seen in Obesity?
Increased Cortisol Production Increased Insulin Resistance Decreased Sex Hormone binding Globulin (women) Decreased Preogesterone levels (women) Decreased Testosterone (men) Decrease growth hormone Production.
What Metabolic disorders are obese individuals at greater risk of developing?
Diabetes Mellitus
Dyslipidemia
Liver Disease
In which genders/Ethnic groups is type 2 diabetes strongly associated with overweight/obesity?
Both Genders
All Ethnic Groups
How does risk for type 2 diabetes evolve?
It increases with the degree and duration of being overweight in individuals.
What is the relative risk increase of Diabetes in a women with a BMI of 22 to a a BMI of 35?
4000% (40 fold)
What is the relative risk increase of Diabetes in a man with a BMI of 24 vs a BMI of 35?
6000% (60 fold)
What is the effect of weight loss on risk of developing diabetes?
Reduces risk.
a weight loss of 5-11kg decreased risk of diabetes development by what percentage?
50%
Dropping 20kg of weight, or having a BMI below 20 does what to risk of type 2 diabetes development?
Makes it almost nonexistent
What is the relationship between HDL and BMI?
Inverse
Inc HDL = dec BMI
Inc BMI = dec HDL
Low HDL carries more relative risk for what condition than elevated triglyceride levels?
Development of heart disease
How does central fat distribution effect triglycerides?
Central Fat distribution results in Lipid abnormalities that may cause decrease HDL and increaesd LDL to result in hyperglycemia.
What is NAFLD?
Nonalcoholic fatty liver disease, descrives liver abnormalities associated with diabetes.
Cross-sectional analysis of these liver biopsies show prevalance rates for Steatosis (75%) Steatohepatitis (20% and Cirrhosis (2%)
What is Brown Adipose?
A type of specialized Adipose tissue which functions as a major storage site for fat. It is deeply vascularized and densley packed with mitochondria. Lipids here release energy directly as heat.
It is used in the heat production for non-shivering thermogenesis and utilization of excess caloric intake via diet-induced themogenesis
What is White adipose?
Specialized connective tissue that functions as a major storage site for fat.
It is used for heat insulation, mechanical cushion, and a major source of stored energy.
How does lipid metabolism in Adipocytes produce Free Fatty Acids for B-oxidation and Glycerol for gluconeogenesis?
Lipoprotein Lipase activates FFA on Adipocytes membrane, which interacts with Acetyl Coa from Glucose, starting a messenger cascade to trigger Lipogenesis which uses its triglyceride storage pool to activate Hormone sensitive lipase, effecting Lipolysis, resulting in the release of both FFA for B-oxidation in muscle and liver, and Glycerol for gluconeogenesis in Liver.
Which adipose tissue is the major bulk of adipose tissue in adult mammals, often observed as a loose association of lipid-filled cells called adipocytes?
White Adipose Tissue (WAT)
Are Adipocytes Vascularized?
Yes, by stromal-vascular cells, and each adipocyte is in close proximity to a capillary.
How are White Adipose Tissues held in place?
A framework of Collagen Fibers
Why is the Adipose organ considered Unique?
Only body tissue that can markedly change mass in adulthood (athlete = 2-3%; morbidly obese = 70%)
Average = 22% men; 32% women
Composed of stromal vascular cells, blood vessels, lymph nodes and nerves.
Blood flow lower than other organs.
Where can fat be located?
Subcutaneous Fat (normal)
Dermal Fat
Intraperitoneal or Omental Fat (visceral)
What is adipocyte Hypertrophy?
An increase in size of existing adipocytes, due to excess triglyceride accumulation in existing adipocytes.
(Positive Energy Balance)
What is adipocyte Hyperplasia?
An increase in the number of adipocytes, due to recruitment of new adipocytes from precursor cells.
What is the half-life of adipocytes?
8.4 years
What happens to adipocytes as we age?
They have blunted ability to proliferate, differentiate and confer resistance to cell death.
How do Stem cells become Mature Adipocytes?
Stem cells are proliferated into preadipocytes, which are then recruited through early differentiation into Immature Adipocytes, then they are lipid filled in Late differentiation to become Mature Adipocytes.
What types of secretions are Adipose responsible for?
Resistin Adiponectin TNF-a Interleukins Fatty Acids Lactate Leptin
What is dysregulation in Obesity characterized by?
It is characterized by an abnormal interplay between energy balance, adipocyte size and number, ECM balance, as well as vasculature and immune cell infiltration.
What composes the ECM of adipocytes?
Proteoglycan molecules/Complex
Polysaccharide molecules
Collagen Fibers
What are the characteristics of normal ECM?
low density connective tissue
high plasticity
what is the effect of hypertrophy on adipocytes?
Hypertrophy causes mechanical stress on the adipocyte membrane, which upregulates TGF-B, leading to upregulation of collagen and other ECM proteins to counter act the expansion.
What is the effect on increased mechanical stress on existing adipocytes?
IncreasedECM pressure, which causes adipocyte death, this results in an increased presence of MMPs and Macrophages to aggregate around dead adipocytes.
Why does inflammation occur during mechanical stress on Adipocytes?
Increased macrophage presence from dead cells produces cytokines, which causes inflammation.
What is a Degnerative condition of the body’s adipose tissue?
Examples?
Lipodystrophy
HIV/AIDS
process where energy can be efficiently stored in the form of fats. It encompasses the process of fatty acid synthesis and subsequent triglyceride synthesis.
Lipogenesis
The breakdown of lipids that involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation.
Lipolysis
The phenomenon of cellular dysfunction due to lipid imbalance; where a surplus of FAA induces apoptosis
Lipotoxicity
What is the relation of M2 macrophages with Lean adipocytes?
Lean adipocytes encourage healthy M2, releasing adiponectin to the M2 while accepting IL-10.
Decreases Lipolysis, Stress, and inflammation
Increases insulin action
What is the relation of M1 macrophages with hypertrophic adipocytes?
Inflammation
Relationship results in an increase of lypolysis, stress, inflammation and a decrease in insulin action.
What are the three approaches to Obesity Treatment?
Behavioral Treatment
Pharmacotherapy
Diet and Excercise
What is the survival paradox?
At older ages, high BMI can be beneficial if no heart disease. as People tend to lose weight to an unhealthy point.
What are the 4 key goals for realistic treatment of obesity?
- 5-10% weight loss
- Focus on Health, Fitness, and Energy Level
- Positive Mood and Appearance
- Functional and Recreational Activities
At what BMI should Diet and Excercise be encouraged?
anything greater than 25
At what BMI should pharmacotherapy be encouraged? With Co-morbidites?
Greater than 30
w/ co-morbids, greater than 27
At what BMI should surgery be recommended? with Co-morbidities?
Greater than 40
w/ co-morbids, greater than 35
What are the components of the pyramid of Obesity Treatment?
Surgery
Pharmacotherapy
Lifestyle modification
What are some common bariatric procedures for obesity treatment?
- Gastric Bypass
- Sleeve gastrectomy
- Adjustable gastric band
- Biliopancreatic diversion with duodenal switch
Within regulation of body weight, match the organ/tissue/balance with the different systems
Brain = Translation System
Energy Balance = Effector System
Peripheral Tissue = Messenger System
When are obesity drugs indicated?
when combined with behavior therapy and diet/exercise changes. Patients must have maintained for at least 6 months before considering pharmacotherapy.
BMI of 30 or greater (27 if co-morbid)
Demonstrate readiness for change
Comply with medication use
No medical or psychiatric contraindications
What additional considerations should be looked at when using anti-obesity drugs?
- Never use with complimentary lifestyle modifications
- Never used as solo therapy
- Must be continually assessed for efficacy and Safety.
- Can be continued if efficacious and safe, discontinued if not.
What Contraindications/Cautions exist for anti-Obesity Drugs?
Pregnancy or Lactation Unstable Cardiac Disease Uncontrolled Hypertension Unstable Severe Systemic Illness Unstable Psychiatric disorder or history of anorexia Incompatible drug therapy (MAOIs Migraine drugs, Adrenergic agents) Closed Angle Glaucoma General Anesthesia
What drug classes are known to cause weight gain?
Psychotropic Medications B-adrenergic Receptor Blockers Diabetes Medications Highly active Antiretroviral therapy Tamoxifen Steroid Hormones
What potential strategies are effective for Obesity Drug Action?
Reducing Food Intake Blocking Nutrient absorption Increase Themogenesis Modulating Fat Metabolism/Storage Modulating central regulation of body weight
What is the action for FDA-approved anorexiant drugs?
Depress food intake by altering neurotransmitter release, reuptake or acting as receptor agonists
Why was Fenfluramine/Phentermine banned?
Valvular heart disease that occurred in 8-32% of patients caused FDA to withdraw approval of this type of treatment in 1997
Orlistat
MOA and Side effects
Blocks absorption of 30% of consumed fat
GI symptoms (oily discharge etc)
Sibutramine
MOA and Side effects
Inhibits synaptic reuptake of norepinephrine and serotonin
Dry mouth constipation, headache, insomnia, increased BP, tachycardia
Phentermine
MOA and Side Effects
Stimulates release of norepinephrine
CNS stimulation, Tachycardia, dry mouth, insomnia, palpitations
Lorcaserin
Serotonin 2C receptor agonist
Dietary behaviors that may contribute to obesity
Increased consumption of sugar sweetened beverages
Continued low consumption of fruits/vegetables
Increased frequency of meals eaten away from home
What factors contribute to the poor food environment in US?
Number of fast food establishments
Lack of access to full service grocery stores selling affordable healthful foods
Less healthy food and beverage advertising to children
What six target behaviors does the CDC focus on in the prevention of obesity?
- Increase physical activity
- Increase consumption of fruits/vegetables
- Increase breastfeeding initiation, duration exclusivity
- Decrease consumption of sugar sweetened beverages
- Decrease consumption of high energy dense, nutrient poor foods
- Decrease television viewing
Non-nutritive sweeteners
Saccharin Cyclamate Aspartame Neotame Acesulfane-K Sucralose Stevia Xylitol
How many pounds of sucrose does the average american adult consume per year?
64 lbs
1/3 from table sugar
2/3 from processed foods
Saccharin
300-fold sweeter than sucrose Bitter aftertaste Heat-Instable Limited to use in non-baked products Bladder cancer in rats, safe in humans
Cyclamate
30-50 fold sweeter than sucrose
No bitter aftertaste
Heat stable
banned by FDA over concerns about bladder cancer (hexylamine). Still sold in many countries around the world
Aspartame
200-fold sweeter than sucrose
Not heat-stable, but products are non-toxic
Aspartame Metabolism
Aspartame –> Aspartate + CH3OH + Phenylalanine
CH3OH –> Formic Acid
Phenylalanine –> Tyrosine –> Dopamine –> NE
or
Phenylalanine –> Phenyl pyruvic acid –> Phenyl Lactate
Neotame
7000-13000 fold sweeter than sucrose
Less metabolic conversion into amino acids
20-30% absorbed
No effect on Phenylketonuria patients
Acesulfane-K
200-fold sweeter than sucrose Heat-stable Not metabolized Used in some beverages Is often combined with other sweeteners due to bitter aftertaste
Sucralose (splenda)
Chlorinated derivative of sucrose
600-fold sweeter than sucrose
Non-metabolized
Heat stable
Stevia (Truvia, Rebiana)
Natural product from Stevia Rebausiana
200 fold sweeter than sucrose
No evidence for genotoxicity
Generally recognized as safe by FDA in 2008
Xylitol
Sugar Alcohol Same sweetness as glucose 40% fewer calories Does not promote dental caries or plaque formation Can be used in diabetics Manufactured by hydrogenation of xylose
What product may be used for fatty acid substitution?
Olestra
Sucrose esterfied with Stearic Acid
Not readily hydrolyzed into fatty acids, so poorly absorbed
Potential for Hypovitaminosis
May cause GI cramping/loose stools
Which anti-obesity drug acts as an irreversible inhibitor of pancreatic lipase so less fats are absorbed in GI tract?
Orlistat
Interactions occur with levothyroxine warfarin and fat soluble vitamins
‘
Used as adjunt to diet/excerise
What guidelines exist for anorexiant agents in management of obesity?
Used as Adjunts
Not for long-term use
Should not replace proper diet
What classes of anorexiant agents exist?
Sympathomimetic amines
Serotonergic agents
How do sympathomimetic Amines (Adrenergic agents) release NE?
They release NE from storage vesicles in the adrenergic neuron and block reuptake of neurotransmitter from the synapse.
Mechanism of Action for Sympathomimetic Amines?
Not well understood, appetite-supressing effect is secondary to CNS stimulation
Amphetamine
Prototypical anorexiant
Use of amphetamin in diet pills banned by FDA
Ephedrine/Pseudoephedrine
diastereoisomer of ephedrine that can be abused to help lose weight (precursor to methamphetamine)
Phentermine
Single weight-loss agent to decrease appetite
Less potential for abuse and addiction than amphetamine
Continued use can lead to tolerance and rebound weight gain.
ADR: Elevated BP, Anxiety, CVD palpitation
CI: Anxiety, HTN, Breastfeeeding, Hyperthyroidism
Phentermine/Topiramate (Qysmia)
FDA approved for treatment of Obesity.
Topiramate dveloped as anticonsulant in epileptic patients which showed weight loss as common side-effect.
Dosed QD
Mazindol (Sanorex)
Schedule IV appetite suppressant approved for patients BMI >30 or >27 with co-morbids
Tolerance develops over time, most effective at start of weight-loss program
Fenfluramine
Withdrawn due to concerns over heart valve disease.
Was popular in Fen-Phen combo.
Sibutramine
Inhibits neurotransmitter reuptake and stimulation of thermogenesis by activating the B3 adrenergic system in brown adipose tissue.
Withdrawn due to CV disease and minimal efficacy
Lorcaserin (Belviq)
Selective 5-HT2c receptor agonist.
FDA approved for BMI >30 or BMI >27 with co-morbs
Dosed BID
CI: SSRI, SNRI/MAOI, St John’s Wort
Rimonabant
Cannabinoid Receptor Antagonist, withdrawn due to concerns over psychiatric side effects
Liraglutide
GLP-1 receptor Agonist
originally developed for type 2 diabetes
Long acting acylated derivative gives t1/2 of 13hrs.
OTC Diet pills and Herbal Remedies Regulation
Not tightly controlled by FDA, up to consumer to be aware of efficacy and safety.
SGLT-2 Inhibitor (Canaglitozin and Dopaglitozin)
Inhibits transporter so glucose ends up in urine and doesnt end up in general circulation
Inhibits glucose reabsorption in Kidney
Treatment for Diabetes II
Diuretic effect –> Lowered BP
Drugs that can cause obesity
Tricylic antidepressants Oral Contraceptives Antipsychotics Anticonvulsants Glucocorticoids Sulfonylureas Glitazones B-blockers
Do weight loss medications help promote long-term thermogenesis?
No, they promote weight loss through effects on appetite, such as increasing satiety and decreasing hunger
Drug of choice for obesity patient with CVD?
Lorcaserin (5HT2c receptor agonist)
Drug of choice for obesity patient with depression?
Phentermine/Topiramate or Phentermine
How to gauge if weight loss medication is effective?
If >5% body weight at 3 months and safe, it may be continued.
How does metformin promote weight loss?
Not entirely understood, likely due to multiple mechanisms.
Animal Models –> AMP-activated protein Kinase
In a review of nine randomized controlled trials on anti-psychotic medications, which drug produced less weight gain?
Ziprasidone produced less weight gain as well as less cholesterol increase.
Anti-epileptic drugs associated with weight loss
Felbamate, Topiramate and Zonisamide
Anti-Epileptic drugs associated with weight gain
Gababpentin, Pregabalin, Valproic Acid, Vigabatrin and Cabamazepine
What AEDs are considered weight neutral?
Lamotrigine, Levetiracetam and Phenytoin
What can be recommended to obese patients with chronic inflammatory diseases like rheumatoid arthritis?
Use of NSAIDs over corticosteroids which produce weight gain.
How is the phentermine weight regain conundrum approached by most doctors?
Intermittent therapy, since it is not approved for long term use and patients would regain weight loss if stopped immediately.
When might it be reasonable for clinicians to prescribe phentermine long term ?
1) No evidence of CVD
2) No serious psychiatric disease or history of substance abuse
3) Patient informed of weight loss medications that are safe/effective
4) Does not demonstrate a clinically significant increase in pulse or BP
5) Demonstrates a significant weight loss
