Transcript Leptin_Signaling_Pathway

Leptin Signaling Pathway Part 1
Leptin: The Beginning
• Identified by Jeffrey Friedman in 1994.
• Circulating peptide hormone secreted almost
exclusively by adipocytes.
• Regulates adipose mass through effects on food
intake and energy expenditure in the brain.
• Clinical phenotypes of leptin deficiency include
hyperphagia, severe obesity, hypogonadism, and
impaired immunity.
• Has a critical role in regulation of reproductive
and immune function in humans.
Parabiosis Experiments
• Used to determine that
there was a circulating
hormone responsible
for controlling food
intake and adipose
tissue mass.
Ob/Ob Mouse Model
• a mutation at amino acid 105 that results in a
truncation of the leptin protein.
– Administration of the recombinant leptin reduced the
food intake and body weight and corrected all of their
neuroendocrine and metabolic abnormalities.
– Suggests that leptin acts as a signal from adipose to
brain regarding quantity of fat tissue stored.
• Flier and Ahima showed that reduced leptin acts
as a signal of nutritional deprivation.
– Resulting in an increase in food intake, decreased
energy expenditure, and suppression of the
reproductive cycle.
Db/Db Mouse Model
• a deletion of the signaling form of the leptin
receptor.
– Unresponsive to endogenous or exogenous leptin.
– Maintains a normal level of leptin in the blood.
Leptin’s Effect
• Leptin acts via its receptor in the hypothalamus which is a
part of the arcuate nucleus (ARH)
• Tranduces peripheral signals into neuronal responses.
– Activates an appetite suppressing pathway
mediated by neurons producing:
• Pro-opiomelanocortin (POMC) to a melanocyte
stimulating hormone
• Cocaine and amphetamine related transcript
– Inhibits an appetite inducing pathway mediated
by neurons producing:
• Neuropeptide Y
• Agouti related protein
Regulation of Energy Intake
• Leptin-deficient animals exhibit intense
hyperphagia with food-seeking behavior and
aggressive behavior when food is denied.
• They have increased hunger and impaired satiety.
– leptin treatment results in normalization of
hyperphagia.
• Leptin-deficient subjects like all foods. After
7days of leptin treatment, they discriminate
between foods they like and dislike.
Why not leptin treatment?
• Very few humans have mutations effecting the
production of leptin. (5-10%)
• Most are leptin resistant. (90-95%)
– Clinical trials have shown that obese people do
lose weight in a dose dependent manner.
– Highly variable in humans due to the difference in
leptin resistance. Leptin could benefit some
obese individuals but is not likely to significantly
alleviate obesity.
Leptin Resistance?
• Leptin fails to reach brain or failure in leptin receptor signaling cascade.
• In humans it is still up for debate.
– Rosenbaum showed that people put on calorie restriction for 6-10
weeks given a low dose of leptin normalizes appetite and energy
expenditure.
• B6 on HFD show leptin resistance in 3 stages.
1. Gain weight but show normal response to exogenous leptin
2. Show peripheral leptin insensitivity, expressed by changes in food
intake and body weight or by lack of activation of signal transducer
and activator of transcription (STAT)-3, however these mice retain
the capacity to respond to central leptin injection.
3. Develop central leptin resistance and do not show changes in food
intake and body weight in response to exogenous leptin.
Energy Expenditure and Fat Oxidation
• Leptin’s effect is not the result of its appetite
effects alone.
– Food restricted Ob mice show smaller decreases
in body weight and adipose deposits than leptin
treated Ob mice.
– Leptin treatment causes specific loss of fat mass
where food restriction causes loss of both lean
and fat mass.
– Food restriction also causes a decrease in energy
expenditure.
Fatty Liver
• Ob mice develop massively enlarged livers
engorged with lipid, along with depositing
lipid in adipose, muscle and other peripheral
tissues.
– Build up of lipid in nonadipose site contributes to
many of the health consequences of obesity such
as insulin resistance and NAFLD
– After 12 days of leptin treatment the livers are
histologically indistinguishable from wild-type.
– Interestingly, our Btbr Ob animals do not have a
fatty liver. Why?
Leptin mediated weight loss
• Food restriction leads to a rise in serum free
fatty acids.
• Leptin mediated weight loss is not associated
with a rise in free fatty acids or ketones,
suggesting a unique mechanism of fatty acid
oxidation
Leptin and SCD-1
• Cohen and Friedman
– Goal: Elucidate the mechanism whereby leptin
reduces hepatic lipid content.
– Used a gene expression array to select genes
whose expression was increased in Ob compared
to wild-type and then corrected by leptin
administration.
– The top gene on their list was SCD-1.
SCD-1
• Rate limiting step in the biosynthesis of
monounsaturated fats. Make palmitoleic
(16:1)and oleic acid(18:1).
• These are the most abundant fatty acids found
in triglycerides, cholesterol esters, and
phospholipids.
• SCD-1 is regulated by SREBP-1 and PUFA.
Leptin’s effect on SCD-1
• SCD-1 RNA levels highly elevated in untreated
ob livers.
• SCD-1 RNA levels in leptin treated animals
were normalized by 2 days and below lean
controls by 4 days.
• SCD-1 activity was also measured and
followed the same pattern as RNA levels.
SCD-1 repression
• Asebia (abj/ abj) are SCD-1 knockout.
– Have reduction in body fat relative to littermate
controls.
– Also a decrease in plasma leptin levels.
– A result of leptin treatment is a suppression of
hepatic SCD-1 RNA and enzymatic activity . SCD-1
KO/Ob animals resemble leptin treated Ob
animals.
SCD-1 KO/Ob Animals
• Reduction in percent body fat.
• Increase in lean body mass
– Confirmed that reduced adiposity in Ob mice
lacking SCD-1 was not the result of a growth or
developmental defect.
• Food intake-ate more than Ob controls and
weight less
• Energy Expenditure-increase oxygen
consumption and correction of the
hypometabolic Ob state.
SCD-1 and Fatty Liver
• Livers from double KO were indistinguishable
from wild-type mice.
• TG levels were reduced 3-fold compared to Ob
mice.
• Thus, downregulation of SCD-1 activity plays a
major role in leptin-mediated depletion of
hepatic lipid.
Lipodystrophy
• Partial or complete loss of adipose tissue
– Associated with hepatic steatosis, insulin
resistance, diabetes, and leptin dificiency. Is this
due to the absence of adipose tissue as a TG
storage depot or to the absence of an adiposederived factor?
• The result was due to the reduction in leptin
as leptin treatment through injection or fat
transplant corrected the hepatic steatosis,
diabetes and improve insulin resistance.
• SCD-1 deficiency in mice makes them
resisitant to both hepatic steatosis and
obesity. How?
• Fates of hepatic fatty acids
1. accumulation in liver
2. packaged into VLDL for transport
3. be oxidized
SCD-1 products are required for TG and cholesterol
ester synthesis and VLDL production.
Confirmation
• Tyloxapol (inhibits VLDL hydrolysis) experiments
show increased synthesis in Ob mice but a reduction
in the abj/Ob KO animals to the level of control
animals.
• Previously shown reduction in liver TG accumulation.
• Reduced adiposity and increase energy expenditure
in the setting of normal to increase food intake is
suggestive of enhanced fatty acid oxidation.
• SCD-1 KO mice have increased plasma ketone bodies.
Possible Alternative Mechanisms
• Inhibition of SCD-1 could increase levels of
peroxisome proliferator-activated receptor
alpha (PPARa) which leads to increased
peroxisomal fatty acid oxidation.
– PPARa is required for leptin-mediated fatty acid
depletion in the liver.
• Inhibition of SCD-1 may increase activity of
AMP-activated protein kinase, which has been
shown to stimulate fatty acid oxidation
following leptin adminstration.
Citations
• Leptin:a pivotal regulator of human energy homeostasis
– Sadaf Farooqi and Sephen O’Rahilly, The American Journal of Clinical Nutrition
• Leptin and the Control of Metabolism: Role for Stearoyl-CoA
Desaturase-1 (SCD-1)
– Paul Cohen and Jeffrey M. Friedman, The Journal of Nutrition
• Leptin at 14 y of age: an ongoing story
– Jeffrey M Friedman, The American Journal of Clinical Nutrition
• Leptin Suppresses Stearoly-CoA Desaturase 1 by Mechanisms
Independent of Insulin and Sterol Regulatory Element-Binding
Protein-1c
– Sudha B. Biddinger, Makoto Miyazaki, Jeremie Boucher, James M. Ntambi, and C. Ronald
Kahn.
Leptin signaling through JAK–STAT and MC4-R Pathway. Leptin binds to its receptor (Ob-Rb) to initiate
several signaling pathways, including the Janus kinase (JAK)–signal transducer and activator of transcription
(STAT) and melanocortin pathways. JAK–STAT signaling regulates the transcription of numerous proteins,
including insulin-like growth factor-I (IGF-I) and suppressor of cytokine signaling (SOCS). SOCS proteins, in
turn, suppress the JAK–STAT pathway. Leptin also stimulates melanocortin-4 receptor (MC4-R) signaling, which
is antagonized by agouti-related peptide (AgRP).