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By Sigal Fishman, MD

Resistance to Leptin Action is the Major Determinant of Hepatic Triglycerides Accumulation in vivo. By Sigal Fishman, MD. Insulin resistance/Syndrome X. Obesity/abdominal obesity Diabetes (Type 2) Hyperlipidemia (low HDL) Hypertension (increased AGT) Thrombosis (increased PAI-1)

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By Sigal Fishman, MD

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  1. Resistance to Leptin Action is the Major Determinant of Hepatic Triglycerides Accumulation in vivo. By Sigal Fishman, MD

  2. Insulin resistance/Syndrome X • Obesity/abdominal obesity • Diabetes (Type 2) • Hyperlipidemia (low HDL) • Hypertension (increased AGT) • Thrombosis (increased PAI-1) • Inflammation (Cytokines) • NAFLD • Leptin resistance (High leptin; develops with insulin resistance)

  3. Resistance to both, insulin and leptin action may be implicated in accumulation of hepatic TG • Which one is the major determinant??

  4. Leptin role:

  5. Browning JD JCI 2004

  6. Insulin action on glucose metabolism Peripheral Hepatic Glycogen synthesis Gluco-neogenesis glycogenolysis Glycolysis

  7. Clamp studies • Hyperinsulinemic clamp assesses peripheral insulin action and hepatic • Insulin infused at a fixed rate (3mU/kg/min) • In insulin resistant states, the amount of glucose required to maintain euglycemia is much lower. • In insulin sensitive states, glucose is driven into the cells, higher rate of glucose infusion required to maintain euglycemia • Glucose fluxes in to the peripheral tissues assessed by the use of tracers.

  8. Clamp studies • Blood glucose is a balance between Tissue glucose uptake (RD) and Hepatic glucose production (HGP)+ Glucose infusion rate (GIR). • When hepatic glucose production goes down, glucose infusion rate should be increased to maintain euglycemia.

  9. Diet 25% glucose _ Insulin action + a. Glycogenolysis Liver b. Gluconeogenesis Muscle a. Glycolysis b. Glycogen syntase

  10. Insulin glucose isotopes infusion Blood Sample

  11. Somatostatin Insulin 3mu/kg/min+glu Tritiated glucose infusion 3 H2O IV catheter VF- Recovery Day -3 Day 0 Day of the clamp

  12. Relationship between hepaticTG and hepatic insulin action r=-0.57 p=0.01 Old Young

  13. 1 Leptin reduces hepatic TG and improves hepatic insulin sensitivity in young lean rats

  14. Effect of chronic leptin delivery on the hepatic TG * P<0.01 vs. all

  15. Effect of chronic leptin delivery on the insulin-mediated suppression of HGP P<0.001 vs. all

  16. Role for SCD-1 in mediating leptin action: VLDL Storage TG Monounsaturated Fatty acid SCD-1 Saturated Fatty Acyl CoA ACC CPT-1 Acetyl-CoA Malonyl-CoA Oxidation Cohen P. J Nutr 2004

  17. young 1.5 leptin 1 pair-fed 0.5 0 Effect of chronic leptin delivery on hepatic SCD-1 expression SCD-1 p<0.001 vs. young

  18. Effect of chronic leptin delivery on hepatic ACC-1 expression 1.4 1.2 young leptin 1 pair-fed 0.8 0.6 0.4 0.2 0 ACC-1 p<0.001 vs. young

  19. young leptin Pair-fed Effect of chronic leptin delivery on hepatic ACC2 expression 7 6 5 4 3 2 1 0 ACC2 P<0.05 vs. young

  20. Effect of chronic leptin delivery on hepatic Malonyl Co-A levels * P<0.01 vs. all Barzilai et al. JCI. 100:3105, 1997

  21. Jiang G. JCI 2005

  22. Leptin: • Improves hepatic insulin sensitivity. • Decreases hepatic TG stores What happens in leptin resistant states?

  23. Leptin’s effect on insulin suppression of glucose production in aging Leptin vs. pair-fed 0 * -20 -40 % Suppression -60 -80 -100 Young Old

  24. TG levels after leptin administration in aging rats

  25. 1B ** 9 ## 8 7 6 5 Hepatic TG Content (mg/gr) * 4 1A 3 # 2 1 0 12 0 2 4 6 8 10 HGP (mg/kg/min) Young– pair-fed Old– pair-fed Young– leptin Old – leptin

  26. 2 Improvement in hepatic insulin action by visceral fat removal is associated with reduction in hepatic TG content in old obese rats…but also with improvement in leptin sensitivity

  27. Epidydimal fat removal

  28. Visceral fat • Associated with insulin resistance, abnormal glucose tolerance and diabetes across all ages. • VF, in adolescents, correlates with insulin resistance. • Increased visceral fat seen in aging. • VF is associated with increased risk of hypertension, thrombosis and dyslipidemias. • Labile fat depot.

  29. Are the fat depots biologically distinct? • Sprague-Dawley rats were sacrificed after 12 hours fast. • RNA was isolated from perinephric (visceral fat) and subcutaneous adipose tissues. • Experiments were performed using rat genomic microarrays (RGU34A), a platform containing 9000 genes (Affymetrix, Santa Clara, CA). • Results of gene array expression involving genes implicated in insulin resistance (PPAR-g, leptin)or it’s syndrome (angiotensinogen and plasminogen activating inhibitor-1 {PAI-1}), were confirmed and quantified by real time PCR. • Some of the genes that are involved in glucose metabolism but were not part of the gene array platform, such as Resistin and Acrp 30, were studied by real time PCR.

  30. Out of approximately 8,000 full-length sequences and approximately 1,000 EST clusters 1660 were expressed 297 wereup/down- regulated ineach chip Atzmon et. Al Horm Metab Res. 2002; 34:622

  31. Atzmon et. Al Horm Metab Res. 2002 34:622

  32. Visceral and SC fat are biologically distinct • Visceral fat and subcutaneous fat are biologically distinct. • Some of the significant changes are in the expression of fat-derived peptides that may have a role in insulin resistance (PPAR, leptin, resistin, and adiponectin) or its syndrome (PAI-1 and AT) and in factors affecting body fat distribution (leptin,  adrenergic receptors, PPAR, IGF-1, GH).

  33. Factors affecting expression of FDP • Is there a role for nutrients in the expression of FDP? • How do nutrients affect the two fat depots? • Is the effect of nutrients on the two depots different? • How do adipocytes “sense” excess nutrients?

  34. Glucosamine Glucose Glucose-6-P GFAT FFA Glc -1-P -6-P F 1-3% GlcN -6-P UDP- Glc Triose -P UDPGlcNAc Glycogen Glycolysis FFA Hexosamine Biosynthetic Pathway Glycosylation sp1

  35. Nutrients, nutrient sensing, and induction of fat-derived peptides Saline Saline Saline Saline Saline Saline Leptin Resistin Glucose Glucose Glucose Glucose Glucose Glucose Gene expression (adjusted by GAPDH) Gene expression (adjusted by GAPDH) $@ Insulin Insulin Insulin Insulin Insulin Insulin $$$ 12 GlcN+In GlcN+In GlcN+In GlcN+In GlcN+In GlcN+In @ 60 10 50 $$$ $$ 8 $ 40 *@ $$ 6 30 4 20 $$ $$ $ 2 10 0 0 VF SC VF SC VF Angiotensinogen  TNF- Acrp30 Gene expression (adjusted by GAPDH) Gene expression (adjusted by GAPDH) Gene expression (adjusted by GAPDH) Gene expression (adjusted by GAPDH) $$@ 20 6 $@@ 18 * 16 5 @ *@ 16 14 $$ 14 4 $$ 12 12 $$ $$ 10 10 $@ 3 $$ 8 8 2 6 6 4 4 1 2 2 0 0 0 SC VF SC VF SC VF PAI-1 50 Gene expression (adjusted by GAPDH) 45 40 35 30 *@ 25 16 14 12 10 $$ 8 6 4 2 0 SC ADA, 2003

  36. What are the biological reasons for the risks determined by increased VF? VF expresses higher harmful fat-derived peptides. Nutrients induce the expression of fat-derived peptides more in VF than other fat depots.

  37. Increased Visceral Fat Glucose FFA Nutrient sensing (HBP?) . Thin fibrous cap . Unstable plaque . Impaired fibrinolysis . Increased collagen . Endothelial dysfunction NEFAs NEFAs PAI-1 IL-6 adiponectin TNF- Skeletal Muscle Liver Adiponectin Resistin leptin TNF- TNF- Leptin HL IR LPL Apo B Insulin TG Glucose The metabolic syndrome

  38. Insulin’s Suppression of Hepatic Glucose production After VF removal Old AL Old VF- * 12- 10- 8- 6- 4- 2- 0- HGP (mg/kg/min) P<0.01

  39. Old AL Old VF- Old SC- * 8- 6- 4- 2- 0 TG (mg/g liver) P<0.01 vs. VF- Reduction in Hepatic TG After VF removal

  40. Plasma FFA levels in this model (old VF-) do not relate to changes in hepatic TG FFA (mmol/l) old VF- old AL Basal: 1.06 ± 0.13 0.83 ± 0.6 clamp: 0.77 ± 0.11 0.65 ± 0.1

  41. Old AL VF- VF- VF- VF+ Leptin 6 E P M SC E P M SC E P M SC ß-actin 5 4 * 100 * 80 3 60 M SC 2 40 1 20 0 0 Leptin (expression)-VF- Leptin (ng/ml) Removal of visceral fat in rats results in coordinated changes in leptin level and leptin gene expression of SC fat. Decrease levels of hormone may be an index for improvement in its action!

  42. VF removal might improved leptin sensitivity: • Hormone level decreased ,combined with reduction in SC gene expression • No change in food intake! • In this model we can not dissociate again, insulin action from leptin role

  43. 3 Improvement in hepatic insulin Does not improve hepatic TG content in leptin resistant ZDF rats

  44. ZDVF+ ZDVF- 16 125 12 14 100 * * 10 12 75 10 8 50 8 6 25 6 4 0 4 Insulin (µU/ml) EGP (mg/kg/min) Glucose (mM) ZDVF+ ZDVF- GIR 0 2.1 ± (mg/kg/min) Removal of visceral fat improves glucose tolerance in Zucker diabetic rats .

  45. TG levels after VF extraction in ‘leptin resistance’ Zucker rats. Hepatic TG stores improves by leptin independent of insulin sensitivity

  46. ** 22 2B ## 17 10 9 * 2A 8 Hepatic TG Content (mg/gr) # 7 6 5 4 $ 3 2 0 2 4 6 8 10 12 HGP (mg/kg/min) Old – shamoperation ZDF– sham operation Old – VF- ZDF – VF-

  47. Summery • Leptin and insulin resistance occur together with obesity and overfeeding. • Leptin decreases hepatic TG stores by decreasing lipogenesis and increasing ß-oxidation.(leptin studies in young) • With leptin resistance hepatic TG stores are not decreased (in old obese animals). • Reversal of insulin resistance is associated with decreasing hepatic TG stores. (Visceral fat removal) • It is the leptin action and not the insulin action that modulates hepatic TG stores(in Zucker NASHI rats).

  48. Thank you!!! Nir Barzilai Radhika Humuzumdar Gil Atzmon Xiao-Hui Ma Xiao-man Yang Hong qiang Liang

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