Obesity Flashcards
Homozygous (cmpd heterozygous) LOF mutation in LEP gene or LEPR gene
-Congenital Leptin and Leptin Receptor Deficiency
-Rapid WT gain
-First few months of life
-Severe obesity
-Hyperphagia
DX: sequencing
Tx: Leptin (LEP def)
MC4R agonist setmelanotide
Treatment for LEPR deficiency
Suppress hunger and WT loss
Homozygous or cpmd heterozygous mutations in POMC
Hyperphagia & early onset obesity
Enzymes for processing POMC
Prohormone convertase 1 (PCSK1)
PCSK2
Carboxypeptidase E
PCSK1
Necessary for production of ACTH from POMC (pituitary)
PCSK2
Acts on products of PCSK1 (hypothalamus)
Produce melanocortin peptides (yMSH, aMSH, BMSH)
Deficiency in PCSK1
Disrupts POMC
-hyprephagic/early obesity
-ACTH deficiency
-HYpogonadotropic hypogonadism
-High postprandal glycemia (increased proinsulin low insulin)
Treat PCSK1 deficiency
Setmelanotide
MC4R deficiency
LOF mutation in MCR4
-early onset of obesity
-Most common gene in which variants contribute to obesity
-Agonized by POMC peptides
SIM1 Deficiency
Sx: Hyperphagia, Severe Obsesity, speech and language delay, neurobx abdnormalities
(like prader willi)
SIM1
Transcription factor
Role in the development of hypothalamus where MC4R is highly expressed
BDNF & TrkB Deficiency
Brain-derived neurotropic factor
Tropomycin-related kinase B
Associatd with Hyperphagia & obesity, learning dx
De novo mutation (consider when parents are normal WT/IQ)
SH2B1 Deficiency
Hyperphagia, severe early onset obesity and insulin resistance
SH2B1
Src-homology-2 (SH2) B-adaptor protein
Intracellular adaptor protein
Mediates signaling through a number of receptor tyrosine kinases (including TrkB) and cytokine receptors (LEPR)
NAFLD
Fructose metabolized by fructokinase
bypasses regulation in the liver
Contributes to insulin resistance
Phosphofructokinase 1 (PRK-1)
Tightly regulates glucose metabolism
Inhibited by ATP & Citrate
When E is sufficient, dietary glucose will bypass the liver
