Pathophysiology Flashcards
Increased visceral fat signalling
↑ IL-6, TNF-a
↑ FFA = oxid stress, IR
↑ leptin = inflammatory
Insulin resistance
↓ adiponectin
… tons of others on slide 8, 20 (+ROS, +RAAS, +gluconeo)
4 ways microbiota can lead to obesity
- ↑ E harvest
- ↓ AMPK leading to ↓ FFA ox & ↑ fat storage
- Altered gut hormones
-eg SCFA from bact = ↑ GLP1 & PYY
-suppress FIAF (fasting-induced adipose factor) –| LPL –> TG storage
(i.e. disinhibition when FIAF suppressed) - Inflammation 2/2 LPS –> ?impared glucose tolerance, ↓ gut barrier
Def & Proposed mechs (3) of leptin resistance
def: high levels of leptin do not cause expected anorexigenic wt loss leading to
-↑ food
-↓ E exp
-IR
-↑ adipose tissue
mechs:
1- chronic receptor overstim –> ?downstream deact
2- impaired crossing BBB
3- hypothalamic inflammation
Adiponectin in obesity
↓ with ↑ adiposity
results in:
↑ in TNF-a
↑ tumor prolif & aggressiveness (breast, gastric, lung)
-dyslip & athero
3 other cytokines & fcn
- Chemerin: ↑ adipogenesis and MPh infil.
- Omentin: ↓ in ob = ↑ IR, vasoconstriction
- Vaspin: ↑ IR
Mechs of Obesity –> IR/DM continuum
- ↑FFA –> ectopic fat in mm, liv, b-cells –> ↓ ins sens
- ↑ Leptin -> aldo -> ↑ SNS -> ang II –| ins receptors)
Mechs of Obesity –> HTN
?
- ↑ ROS produced –> pro inflammatory signaling –> monocytes promote infl. changes in endoth* (↑ MCP-1)
*also by dysreg adipokines:
↑ leptin
↑ chemerin
↓ adiponectin
↓ omentin-1
- PVAT ↓NOS & ↑TNF = ↑ ox stress = ↑ infl = ↑ contractility
- ↑ Leptin -> ↑ SNS central & periph -> vasoconstr
- WAT & mech renal compresson -> RAAS activated with ↑ aldo -> ↑ Renal Na retention
SNS activated directly by
?
-RAAS
-↑ Leptin
-OSA
-Insulin
Obesity & Dyslipidemia
-% prev
-what’s ↑, nL, ↓
-location of adipose
-60-70% of pts w ob (50-60% w pre-ob)
-↑ TG, VLDL, ApoB, non-HDL
-freqently nL LDL (but ↑ small dense LDL)
-↓ HDL, Apo A-I
-visceral & upper subQ -> ↑ IR ↓HDL
-leg subQ -> ↓ TG
Obesity –> “Adioposopathic” Dyslipidemia
↑ Circulating FFA
–> ↑ FFA in liver (steatosis)
–> Liver:
↑TG production (via insulin -> SREBP-1c)
↑VLDL release
–> ↑ serum TG (LPL in capillary beds can’t keep up)
–> VLDL exchanges TG for chol from HDL & LDL via CETP
==> ↓ HDL and ↑ small dense LDL
LPL
-location
-activated by (4)
-capillary beds (incl adipose)
-activated by:
1. exercise
2. insulin
3. fibrates
4. omega-3’s
NAFLD in Obesity
-prev
-mechs
-60-80% w DM & ob
-100% w severe obesity
*genetic, dietary, metabolic, and hormonal factors
Ectopic fat accumulation + low-grade chronic infl.
–> hepatocytes vulnerable to lipid ox, ↓ apop, cytokines
For example, VAT:
↑ FFA, IL-6, TNF-1, resistin
↓ Adiponectin
NAFLD 2-hit hypothesis
- ↑ TG in liver via
-IR, hyperins
-↑ FFA uptake
-↑ de novo lipogenesis
-↓ FFA ox
-↓ VLDL secretion - Hepatocyte injury via:
-gut toxins
-↑ cytokines
-mito dysfcn
-ox damage
-dysreg apop
Obesity-related cancers (13)
-% in us (2014)
-40% of CA in US have obesity as risk factor
-↑ incidence for these cancers vs. other CA’s ↓
Meningioma
Thyroid
Breast (p-meno)
Esoph adenoCA
Upper stomach
Colon and rectum
Liver
Gb
Panc
Kidneys
Uterus
Ovaries
MM
Obesity & CA mechs (3)
- Endocrine via ↑ in all:
-insulin
-IGF-1
-estrogen
-androgens in women
-leptin (+tumor growth for breast & colon CA) - Adipokines & Chronic Inflammation (DNA damage, mutations, ROS, angiogen, etc)
↑ IL-6
↑ TNF-a
↓ CRP
↓ adiponectin
- cytokines promote endoth dysfcn, ECM abnL, intrav (mets)
- hypoxia from adipocyte growth -> immune & angiogenesis responses -> tumor progression
- ↑ exposure time to impaired fasting glucose = ↑ CA risk, esp colorectal
3 main causes of ALL obesity-related complications
1- chronic inflammation
2- IR (for example, via ↑ FFA)
3- SNS activation
Effects of Sleep Deprivation
-Stim appetite via:
↓ leptin
↑ Ghrelin, orexin, NPY
-EE ↓
-↑ fat/sugar/salt food choices
-also ↑ cortisol
*sleep quality less assoc.
OSA
-#1’s
-risks
1 sleep disorder
#1 RF is obesity
-CV dz, M&M, ↓ life exp
*Dose response ↑ wt = ↑ severity
Effects of glucocorticoids (4)
-redist WAT to visc
-↑ appetite (esp comfort foods), can ↑ NPY
-↑ IR & leptin resistance
-wt gain
Factors that ↑ cortisol (5)
-↓ sleep
-chronic stress
-chronic pain
-high GI foods
-inflammation
Cortisol levels in obesity
-↑ in 50%!! = highest risk of met syn & CV dz
(other half have nL cortisol)
Most robust obesity gene locus
FTO
*diet composition strongly affects influence
Rare genetic causes of obesity
-#?
-common sx
> 20 rare disorders
-severe, early onset often <1yo
-insatiable hunger (hyperphagia)
Monogenic disorders
-LEP/LEPR mutation
-POMC deficiency
Extremely Rare:
-PCSK1 (<20 worldwide)
-SIM1 (<50)
-NTRK2 (<10)
Oligogenic disorder
MC4R
** most common, 2-3% of children & adults
Genetic syndromes (8)
Prader-Willi
Bardet-Biedel
Cohen
Alstrom
X Frgile
Borjeson-Frossman-Lehmann
Albright hereditary osteodystrophy
?downs, turners, achondro??
Unique to kids
-obesity can ↓ neuroplasticity
-early adiposity rebound is marker for later obesity
Mech of disrupted menstrual cycle
IR affects HPA axis:
↑ LH
↑ theca cell stim
↑ circ andro’s
–> abnL bleeding, ameno, ↓ fertility
PCOS & Obesity
-prev
-risks
1 endocrinopathy in childbearing-age women
30-60% of women with obesity!
Risks of Obesity WITH PCOS:
↑ SAB’s
↑ gest HTN
↑ gest DM
↑ prematurity
Male hypogonadism (3 mechs)
-bidirectional
- ↑ insulin –> ↓ SHBG production in liver –> bioavailable testosterone
- Adipose tissue ↓ test b/c converts free test –> estrogen
- Leptin, IL-6, TNF-a –| gonadal steroidogenesis via pituitary
(↓ kisspeptin –> ↓ GnRH –> ↓ LH pulse amplitude)
Effects(causes?) of low T (4)
-IR & impaired glucose control
-Dyslipidemia
-HTN
-CVD
Unique in Men
↑ VAT
↓ adiponectin
High fat meal ↑markers of inflammation/angiogen
↑ risk of CKD, COPD
% of all US cancers w obesity as risk factor
% of pts with Obesity who also have:
-PCOS
-Dyslipidemia
-NAFLD
40% of CA
-PCOS in 30-60% of pts w obesity
-Dyslipidemia in 60-70% (50-60 w pre-ob)
-NAFLD in 60-80% with DM AND Obesity (100% w severe obesity)
