Adipostatic action of Leptin: Leptin signals fat-storage sufficiency

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Adipostatic action of LeptinLeptin signals
fat-storage sufficiency
leptin
(Nature 404 661, 2000)
2
Leptin effect in the arcuate nucleus of the
hypothalamus 1. direct effect
(Science 30463-4, 2004)
3
Leptin effect in the arcuate nucleus of the
hypothalamus 2. neuroplasticity
(Science 30463-4, 2004)
4
Leptin effect in the arcuate nucleus of the
hypothalamus 3. Neuronal wiring during a
critical post-natal period body weight set
point?
(Science 30463-4, 2004)
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Leptin in human obesity

• Circulating leptin levels are regulated by fat
  mass, gender, fed-fasted state.
• Although loss-of-function mutations in the leptin
  or leptin-receptor genes have been described,
  this is likely a very rare cause of human
  obesity.
• Common human obesity is associated with elevated
  circulating leptin levels, which are believed to
  represent a state of leptin resistance.
• ? Leptin therapy trials are largely ineffective
  in common human obesity

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Leptin-induced signal transduction pathways
Overexpression of SOCS3 could be a mechanisms for
leptin resistance (Nat. Med. 10 734, 2004)
(Cell Biol. Int. 28 159, 2004)
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Adiponectin

• - A complement-related protein secreted
  specifically from adipose tissue, reaching high
  circulating concentration (0.01 of total plasma
  proteins).

Adiponectin trimeric form

• Low circulating adiponectin is found in patients
  with
• Central adiposity, Insulin resistance, Type 2
  diabetes, Hypertriglyceridemiam, Hypertension and
  Coronary artery disease.
• Low adiponectin is an independent risk factor for
  MI Adjusted RR 0.56 (0.32-0.99, plt0.02) for
  highest Vs. lowest quintiles of adiponectin
• (JAMA 291 1730, 2004)

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Can low adiponectin be causatively linked to the
metabolic syndrome?
Adiponectin KO mice are insulin resistant...
(J. Biol. Chem. 27725863, 2002)
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Adiponectin signals readiness for (safe) fat
handling?
Brain
Liver
Adipose tissue
Endothelium
Muscle
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Resistin a putative insulin resistance factor

• Mediates resistance to insulin Discovered
  through a search of genes down-regulated by
  Thiazolidindiones. (Nature 409 307, 2001)
• Controlling fat mass Shown as a secreted product
  (termed ADSF) inhibiting adipogenesis. (JBC 276
  11252, 2001)
• An inflammation modulator Induced during lung
  inflammation (FIZZ1). (EMBO-J 19 4046, 2000)

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- A genetic loss-of-function approach
Science 203 1195-8, 2004))
Fasting plasma glucose
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Suggested mechanism for resistin-mediated link
between obesity and diabetes
?
SOCS3
AMPK
(adopted from J. Intern. Med. 255 439-47,
2004 MCB 25 1569-75, 2005)
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Open questions on the biology of resistin in
human obesity

• Human resistin is only 64 identical in sequence
  to the mouse resistin.
• It is expressed in low levels in fat tissue, and
  highly in circulating and bone-marrow monocytes,
  lung, and other tissues. ? is it really a human
  adipokine?
• Contradictory findings in humans on the
  regulation of circulating resistin levels, though
  recent studies seem to correlate higher levels
  with insulin resistance and the metabolic
  syndrome.

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Fat tissue is a metabolic-endocrine organ. Both
hypo- and hyper-adiposity are pathological.
Metabolic abnormalities? Fat deposition
abnormalities? Endocrine abnormalities? The
combination?
Insulin sensitivity
normal
Fat mass / BMI
obesity
lipodystrophy
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Does therapy correlate with changes in adipokine
secretion?
Metformin Insulin/SU TZDs Weight loss
? / ? ? (weight loss) ? ? / ? ? Leptin
? ? ? ? / ? Adiponectin
? ? ? / ? Resistin
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Thank you!
Special thanks to Dr. Hannah Kanety and to Prof.
Nava Bashan for help in preparing this talk