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Adipokines & Insulin Signaling Pathways

Click on one of the adipokines shown in the Explore Pathways box below to see how it affects insulin signaling and metabolism.

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Adiponectin

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

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

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

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

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

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

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

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

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

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

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 R

IRS

SHP-2

GRB2

SOS

Shc

GRB2

SOS

Ras

GDP

Ras

GTP

Raf

MEK1/2

ERK1/2

c-Myc

Max

Elk-1

AP-1

IRS

PI 3-K

PIP₂

PIP₃

PDK-1

PTEN

Akt/PKB

TOR

p70 S6K

RPS6

PKC

GSK-3 (Inactive)

FoxO1/FKHR

FoxO1/
FKHR

eIF2B (Active)

Glycogen
Synthase (Active)

Glucose

Glycogen

CBL

CAP

Crk

C3G

TC10

GDP

TC10

GTP

Glut4

AMPK (Skeletal Muscle)

Glucose Uptake

Exercise

Protein Synthesis

Cell Proliferation,
Differentiation

Anti-apoptotic Signal

Protein Synthesis

Glycogen Synthesis

Apoptotic genes

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

Glut4-containing
vesicles

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.

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