Adipokines & Insulin Signaling Pathways

Click on one of the adipocytokines below to see how it affects insulin signaling and metabolism.

Adiponectin
Adiponectin

Enhances Insulin
Sensitivity

Enhances Insulin
Sensitivity

Adiponectin

  • Increases fatty acid oxidation in
    muscle & the liver
  • Decreases hepatic glucose output
  • Increases glucose uptake in muscle
  • Activates AMPK & PPAR alpha in muscle &
    the liver
  • Anti-inflammatory

Adiponectin

  • Increases fatty acid oxidation in
    muscle & the liver
  • Decreases hepatic glucose output
  • Increases glucose uptake in muscle
  • Activates AMPK & PPAR alpha in muscle &
    the liver
  • Anti-inflammatory
Angiopoietin-like 2
Angiopoietin-like 2

Inhibits Insulin
Sensitivity

Inhibits Insulin
Sensitivity

Angiopoietin-like 2

  • Circulating levels correlate with adiposity
    and insulin resistance
  • Pro-inflammatory

Angiopoietin-like 2

  • Circulating levels correlate with adiposity
    and insulin resistance
  • Pro-inflammatory
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IL-6
IL-6
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IL-6

  • Circulating levels correlate with obesity and
    insulin resistance
  • Promotes adipocyte lipolysis
  • Increases circulating fatty acid levels
  • Pro-inflammatory

IL-6

  • Circulating levels correlate with obesity and
    insulin resistance
  • Promotes adipocyte lipolysis
  • Increases circulating fatty acid levels
  • Pro-inflammatory
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Leptin
Leptin
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Leptin

  • Decreases appetite
  • Increases thermogenesis/energy expenditure
  • Increases fatty acid oxidation
  • Activates AMPK in muscle & the liver

Leptin

  • Decreases appetite
  • Increases thermogenesis/energy expenditure
  • Increases fatty acid oxidation
  • Activates AMPK in muscle & the liver
Omentin
Omentin

Omentin

  • Promotes insulin-mediated glucose transport
    in adipoctyes
  • Circulating levels inversely correlate with
    obesity and insulin resistance

Omentin

  • Promotes insulin-mediated glucose transport
    in adipoctyes
  • Circulating levels inversely correlate with
    obesity and insulin resistance
PBEF/Visfatin
PBEF/Visfatin

PBEF/Visfatin

  • Non-competitive insulin mimetic
  • May affect glucose-stimulated insulin secretion by
    regulating pancreatic beta cell function

PBEF/Visfatin

  • Non-competitive insulin mimetic
  • May affect glucose-stimulated insulin secretion by
    regulating pancreatic beta cell function
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Resistin
Resistin
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Resistin

  • Impairs glucose tolerance
  • Promotes hepatic insulin resistance in mice
  • Inhibits adipocyte differentiation

Resistin

  • Impairs glucose tolerance
  • Promotes hepatic insulin resistance in mice
  • Inhibits adipocyte differentiation
RBP4
RBP4

Retinol-Binding Protein 4/RBP4

  • Promotes hepatic gluconeogenesis in mice
  • Increased levels are associated with insulin resistance in mice
  • Genetic deletion enhances insulin sensitivity in mice

Retinol-Binding Protein 4/RBP4

  • Promotes hepatic gluconeogenesis in mice
  • Increased levels are associated with insulin resistance in mice
  • Genetic deletion enhances insulin sensitivity in mice
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Serpin A12/Vaspin
Serpin A12/Vaspin
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Serpin A12/Vaspin

  • Administration improves glucose tolerance and
    insulin sensitivity in diet-induced obese mice
  • Anti-inflammatory

Serpin A12/Vaspin

  • Administration improves glucose tolerance and
    insulin sensitivity in diet-induced obese mice
  • Anti-inflammatory
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TNF-alpha
TNF-alpha
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TNF-alpha

  • Deletion of TNF-alpha improves insulin
    sensitivty in mouse models of obesity
  • Promotes adipocyte lipolysis
  • Increases circulating fatty acid levels
  • Inhibits Adiponectin production
  • Decreases Glut4 expression
  • Pro-inflammatory

TNF-alpha

  • Deletion of TNF-alpha improves insulin
    sensitivty in mouse models of obesity
  • Promotes adipocyte lipolysis
  • Increases circulating fatty acid levels
  • Inhibits Adiponectin production
  • Decreases Glut4 expression
  • Pro-inflammatory
Free Fatty Acids
Free Fatty Acids

Free Fatty Acids

  • Increase insulin-suppressed hepatic
    glucose production
  • Decrease glucose uptake
  • Promote the accumulation of
    triglycerides & fatty acid-derived
    metabolites in muscle & the liver

Free Fatty Acids

  • Increase insulin-suppressed hepatic
    glucose production
  • Decrease glucose uptake
  • Promote the accumulation of
    triglycerides & fatty acid-derived
    metabolites in muscle & the liver
Insulin
Insulin
Insulin R
Insulin R
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IRS
IRS
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SHP-2
SHP-2
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GRB2
GRB2
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SOS
SOS
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Shc
Shc
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GRB2
GRB2
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SOS
SOS
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Ras
Ras
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GDP
GDP
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Ras
Ras
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GTP
GTP
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Raf
Raf
MEK1/2
MEK1/2
ERK1/2
ERK1/2
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c-Myc
c-Myc
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Max
Max
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Elk-1
Elk-1
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AP-1
AP-1
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IRS
IRS
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PI 3-K
PI 3-K
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PIP2
PIP2
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PIP3
PIP3
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PDK-1
PDK-1
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PTEN
PTEN
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Akt/PKB
Akt/PKB
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TOR
TOR
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p70 S6K
p70 S6K
RPS6
RPS6
PKC
PKC
GSK-3 (Inactive)
GSK-3 (Inactive)
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FoxO1/FKHR
FoxO1/FKHR
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FoxO1/
FKHR
FoxO1/
FKHR
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eIF2B (Active)
eIF2B (Active)
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Glycogen
Synthase (Active)
Glycogen
Synthase (Active)
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Glucose
Glucose
Glycogen
Glycogen
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CBL
CBL
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CAP
CAP
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Crk
Crk
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C3G
C3G
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TC10
TC10
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GDP
GDP
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TC10
TC10
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GTP
GTP
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Glut4
Glut4
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AMPK (Skeletal Muscle)
AMPK (Skeletal Muscle)
Glucose Uptake
Glucose Uptake
Exercise
Exercise

Protein Synthesis

Protein Synthesis

Cell Proliferation,
Differentiation

Cell Proliferation,
Differentiation

Anti-apoptotic Signal

Anti-apoptotic Signal

Protein Synthesis

Protein Synthesis

Glycogen Synthesis

Glycogen Synthesis

Apoptotic genes
Apoptotic genes

Effects of Insulin Signaling
  • Increases Glucose Uptake in Fat & Muscle
  • Inhibits Hepatic Glucose Production
  • Stimulates the Synthesis & Storage
    of Lipids, Carbohydrates, & Proteins

Effects of Insulin Signaling
  • Increases Glucose Uptake in Fat & Muscle
  • Inhibits Hepatic Glucose Production
  • Stimulates the Synthesis & Storage
    of Lipids, Carbohydrates, & Proteins

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Glut4-containing
vesicles
Glut4-containing
vesicles
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Overview of Adipocytokines & Insulin Signaling

Insulin, secreted by pancreatic beta cells, is the main regulator of blood glucose levels. It inhibits glucose production in the liver, stimulates glucose uptake in muscle and fat, promotes glycogen and lipid synthesis, and inhibits lipolysis. Insulin signaling promotes glucose uptake by activating intracellular signaling pathways that promote translocation of the GLUT4 glucose transporter to the plasma membrane. Additionally, insulin signaling inactivates GSK-3, which keeps Glycogen Synthase active, thereby promoting storage of glucose as glycogen. Insulin signaling can be enhanced or inhibited by adipocytokines secreted by the adipose tissue. The ability of these cytokines to influence insulin signaling suggests that changes in their levels may contribute to the development of insulin-related metabolic disorders such as Type II diabetes. In support of this hypothesis, one of the leading risk factors for Type II diabetes is obesity, a condition characterized by an increase in adipose tissue mass, altered adipocytokine secretion, and chronic inflammation. Obesity is associated with reduced Leptin sensitivity and decreased Adiponectin production, two adipocytokines that normally enhance insulin sensitivity. These changes are coupled with an increase in the production of pro-inflammatory cytokines such as TNF-alpha and IL-6, which can negatively affect adipose tissue functions and promote insulin resistance. Characterizing the mechanisms by which adipocytokines enhance or interfere with insulin signaling pathways is critical to our understanding of how these factors may contribute to the pathogenesis of metabolic disorders.

To learn more, please visit our Adipocytokines Research Area.