Unit 6 - Obesity Flashcards Preview

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Flashcards in Unit 6 - Obesity Deck (32):

what does the loss of the "physiological winter" mean?

in modern society, we no longer burn the fat we gained in summer


what is the definition of obesity?

pathophysiological state defined as excessive adiposity


what are the imperfections of BMI?

-doesn't measure fat content or muscle/fat ratio
-doesn't account for sex and ratio differences in fat content/distribution of intra-abdominal (visceral) and subcutaneous fat)


what are used as measurements of regional obesity?

-waist circumference
-waist:hip ratio
-waist:height ratio
-none give precise estimate of intra-abdominal (visceral) fat


what is obesity an independent risk factor for?

1. DM 2 (most important)
2. CVD (including coronary disease, stroke, CHF)
3. joint and gallbladder disease
4. reproductive disorders (PCOS), pulmonary abnormalities (apnea)
5. 20% of cancer deaths


what are causes of the problem?

genetics: polygenic (only a few rare human mutations lead to severe obesity)
environment: industrial revolution increased incidence 33% in 1990s alone
other factors: differences in gut microflora, adipocyte number


how many dieters gain their weight back? what does this mean?

over 90% gain it back; this means the biological system modulates body weight, and is resistant to weight changes
-regulates both intake and expenditure via endocrine and neural components


how stable is body weight?

remarkably stable in most adults most of the time (intake = expenditure)
-gain 0.4 - 1.8 pounds/year
-occasional weight gain may last a lifetime, b/c once gained, hard to lose


lipostat hypothesis and basic features

regulation of weight around a set point, which can be reset by factors long long-term over-nutrition, leading to weight gain, in fat-to-brain signaling system
-signal: leptin (released by adipocytes; proportional to fat accumulation);
-sensor: leptin receptors (in hypothalamus)
-effectors: hypothalammic factors that control feeding (either orexigenic or anorexigenic) and energy expenditure (same factors affect both)


what are iimplications for obesity in terms of the lipostat?

set point can change in the course of a person's lifetime
-sensitivity of leptin is decreased in obese persons (from 15-20% body fat to 30-35% body fat)
-such that lipostat robustly defends body weight in obese state


ob/ob VS db/db mice

phenotypically identical
ob(ese): don't produce leptin (make truncated, inactive PRO)
-WT is expressed in fat cells only, and released into circulation (usually highly conserved); but if ob/ob, mice behave as if starved (hypothermia, increased feeding, decreased E expenditure and immune function, infertility)
-3x weight increase, 5x fat increase

db (diabetic): don't make leptin receptors
-WT expressed in hypothalamus that controls feeding, and makes membrane receptor


what do injections of leptin into ob/ob mice cause? were these found in db/db mice too?

-decreased feeding
-increased E expenditure and immune function
-decreased body weight (but only of the adipose tissue; lean body mass spared)
-effects are reversible

NOT found in db/db mice (b/c leptin okay, but receptor defective)


how does leptin act?

act on CNS to:
-inhibit AgRP neurons in hypothalamus that produce orexigenic effectors (AgRP, NPY, plus at least 3 others)
-stimulate POMC neurons in hypothalamus that make anorexigenic effectors (POMC, CART, plus at least 3 others)


what are the 3 models for regulatory failure leading to obesity? which is most common? which is rare?

1. failure to make leptin (ob/ob) - very rare, and only in 2-3 extended families
2. inappropriately low leptin secretion for given fat mass - fat expands until "normal" levels of leptin are reached, causing obesity
-explains ob/+ that have half normal leptin, and tend to moderate obesity
3. leptin resistance - most common, relative or absolute insensitivity to leptin at site of action; associated with increased circulating leptin (like DM2)


what is the mechanism of leptin resistance?

chronic overnutrition causes hypothalamic ER stress, activation of unfolded PRO response (UPR), and mitochondrial damage


how is CCK involved in obesity?

satiety signal released from GIT during eating (along with other short-duration, meal-related peptide hormones)
-promotes sense of "fullness" and discourages more eating
-acts indirectly on hindbrain thru sensory nerves


how is ghrelin involved in obesity?

appetite-stimulating peptide hormone released by empty stomach (only GIT-derived factor that stimulates appetite)
-blood levels rise sharply before meals, and fall quickly when food taken in
-baseline levels surge after weight loss (so that full-stomach signal feels like empty-stomach signal before) to stimulate eating
-ghrelin receptor on cells of AgRP neurons that make NPY and AgRP


how is PYY3-36 involved in obesity?

appetite-suppressing peptide hormone (member of NPY family; fragment of larger peptide)
-released in response to food by endocrine cells lining distal SI and colon
-blood levels high between meals, inhibiting eating for 12 hours
-acts on same cells as ghrelin and leptin (like AgRP neurons)
-best candidate for medium-term signal, but importance in humans still controversial


how do leptin and insulin effects compare?

they are the same
-both inhibit neurons that produce orexigenic effectors, and stimulate neurons that produce anorexigenic effectrs


what are the 5 main components of energy expenditure?

1. REE or BMR
2. energy expended in digesting, metabolizing, and storing food
3. volitional exercise (mechanical work and thermic effect)
4. nonexercise activity thermogenesis (NEAT; walking to work, typing, etc.)
5. adaptive (faculative) thermogenesis (in response to cold exposure, and subject to hormonal regulation involving brown and beige fat tissues)


white VS brown VS beige fat cells

white: single large lipid droplet with few mitochondria, little cytoplasm; secretes adipokines (leptin)

brown: for heat production; rich in mitochondria and have high levels of uncoupling PRO UCP1, and multiple lipid droplets
-formed from same precursor cells as skeletal muscle

beige: white adipose that has been partially converted to brown; has increased mitochondria and levels of UCP1, and multiple lipid droplets
-can be "browned" by exercise and cell technology


effects of UCP1 (uncoupling PRO1)

in brown adipose tissue (less is in adults); creates proton leak in physiological process (adaptive, non-shivering thermogenesis) to dissipate electrochemical gradient (promotes re-entry of H+ into matrix)
-energy is released as heat without being coupled with ATP synthesis (maintains body temperature)
-UCP1 expression is controlled many ways


relationship between brown adipose and BMI

BAT presence is inversely correlated with BMI


what are some activators of UCP1?

1. FA-H+ cotransport (activated by FA)
2. exercise (fat "browning")
3. beta3 adrenergic receptors (catecholamines are released in response to cold and overfeeding, to increase lipolysis, release FFA, and stimulate UCP1; also has direct effects)
-limited effect
4. TH receptor
5. PPAR-gamma and retinoic acid receptors


where are most brown adipose tissue deposits?

small deposits in neck region
-exposure to gold greatly increases lipolytic activity
-there is more BAT in women than men, and more in leaner, younger people


how much of the "futile proton cycling" of UCP1 attributes to BMR of rats? what does this mean?

up to 20-25%
-expression of UCP1 is under extensive transcriptional and nontranscriptional controls


what is the main cause of proton leak in muscle tissue?

not UCP1, but adenine nucleotide translocase (ANT)
-most abundant PRO in mitochondria involved in ADP/ATP exchange
-accounts for 1/2 to 2/3 of basal H+ conductance on IMM


effects of protonophores

poke holes in membranes to increase leakage
-dinitrophenol is example, that increased membrane uncoupling and energy expenditure; but had toxic dosage that damages cardiac and liver systems


polygenic inheritance of tendency to obesity

-strong genetic influence is suspected
-no common mutations identified that predispose obesity in humans
-heritability for obesity can be modified by environmental factors
-adopted children weight similarly to biological, not adoptive, parents


what is KSR2/

kinase suppressor of Ras2
-involved in multiple signaling pathways, and variants are associated with severe early-onset obesity
-WT activates AMPK that increases FA and glucose oxidation, to decrease E storage; so if mutated, then increased storage


effects of Qsymia

anti-obesity drug (with Belviq)
-combo of phentamine and topiramate
-act as appetite suppressants by affecting hypothalamic signal
-unknown mechanism


are liposuction and bariatric surgery effective methods to combat obesity?

BS: modifies anatomy of GIT to reduce food intake and/or absorption
-causes severe morbidity and death, and typically reserved if ahve severe medical problems

L: effective only short term, b/c lost fat is regained due to lowered leptin causing increased food intake