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
