This document summarizes the current understanding of adipokines and their role in insulin resistance. It begins by describing adipose tissue as an endocrine organ that secretes adipokines, which can regulate fat mass and insulin resistance. It then discusses several specific adipokines (adiponectin, omentin, visfatin, leptin, resistin, lipocalin-2, retinol binding protein-4, chemerin, TNF-α, IL-6) and how each contributes to insulin resistance through different mechanisms like decreasing insulin receptor activity or modulating glucose transport. Overall, dysfunctional adipose tissue secretion of altered adipokine levels is associated with insulin resistance and related chronic diseases.

1. Adipokines in Insulin Resistance:
Current Updates
By
Prof. Moustafa Rizk
Prof. of Clinical Pathology
Faculty of Medicine, University of Alexandria
9/3/2023

2. Agenda
Adipose tissue as an endocrine organ
Pro-inflammatory adipokines versus
protective adipokines
Pathophysiology of adipokines in the
aetiology of insulin resistance

3. Fat Cell
Development
After fat cells have
enlarged and
energy intake
continues to
exceed
expenditure, fat
cells increase in
number again.
During
growth,
fat cells
increase
in number.
When energy
intake
exceeds
expenditure,
fat cells increase
in size.
With fat loss,
the size of the
fat cells
shrinks, but not
the number.

4. Adipocytes

5. (WAT) depots in humans are shown in orange. Major
subcutaneous WAT includes superficial and deep abdominal
depots and gluteal-femoral depot. Major visceral WAT includes
epicardial, omental and mesenteric.

6. Adipose tissue as an endocrine organ
• Adipose tissue secretes a variety of bioactive
peptides (adipokines).
• Adipokines may locally regulate fat mass by
modulating adipocyte size/number or
angiogenesis and inversely increased fat
mass leads to dysregulation of adipocyte
functions.

7. Adipokines
Adipokines not only regulate lipid metabolism but also
function in a wide array of physiological or pathological
processes as diverse as
 Host defense,
 Inflammation,
 Apoptosis,
 Autoimmunity,
 Cell differentiation,
 Organogenesis
The complex role of adipokines in obesity, inflammation, and autoimmunity . Erin
B.Taylor.March 2021.Clinical Science 135(6):731-752

8. “Adipokines”
 Forms :
1- Proteins
2- Hormones
3- Factors
4- Cytokines
 Act as
1- Endocrine
2- Paracrine
3- Autocrine
 Deposition of excess energy causes adipose tissue
dysfunction low-grade chronic inflammation
 This chronic inflammation insulin resistance by
modulating various metabolic pathways

9. Pathophysiology of adipokines in
the aetiology of insulin resistance

10. 1- Adiponectin
• Adiponectin consists of 244 amino acids and is
located on chromosome 3q27 , a region
associated with type 2 diabetes and CVD .
• In healthy individuals, circulating adiponectin is
normally between 5–30 u g/ml and is lower in
individuals with adiposity, insulin resistance and
type 2 diabetes
• Numerous epidemiological studies suggest that
adiponectin deficiency is associated with
coronary artery disease and hypertension.

11. Hypoadiponectinemia - an
additional CVD risk factor in T2D
 Hypoadiponectinemia is associated with endothelial dysfunction,
greater carotid intima-media thickness(IMT), and coronary artery
disease
 In vascular levels, actions of the adiponectin comprise reduction
in expression of intercellular adhesion molecule-1(ICAM-1),
vascular cell adhesion molecule1(VCAM-1) and E-selectin
 Inhibit the transformation of macrophages into foam cells and
the proliferation and migration of smooth muscle cells which have
a protective effect on atherosclerosis

12. • Thus, low serum adiponectin level is now considered a
CVD risk factor, type 2 diabetic patients with low
concentrations of this protein would have increased risk of
developing premature arteriosclerosis.
• In other words, lower levels of serum adiponectin is an
additional CVD risk factor for the patients with type 2
diabetes

14. 2- Omentin
Circulating omentin levels are decreased in :
1- Obesity,
2- Metabolic syndrome,
3- Type 2 diabetes (T2D)
4- Patients with coronary artery
5- Established carotid atherosclerosis
 Inversely correlated with insulin resistance,

15. 3-Visfatin
 Visfatin is an inflammatory mediator, based on its
localization in macrophages within atherosclerotic
lesion and its ability to induce matrix
metalloproteinase (MMP)-9 in monocytes
 Elevated in
1- Obesity,
2- Insulin resistance,
3- Type 2 diabetes mellitus,
4- Pro-inflammatory states .
 Visfatin is involved in endothelial dysfunction (ED),
which causes progression of atherosclerosis and
therefore plays an important role in different forms of
cardiovascular diseases.

16. 4- Leptin
 Leptin has emerged as a major inflammatory agent
responsible for vascular inflammation, increased oxidative
stress, endothelial dysfunction, and proliferation of vascular
smooth muscle cells (VSMC), resulting in intimate
hyperplasia.
 Patients with T2DM may be more risky for vascular
inflammation mediated by leptin/adiponectin axis and
subsequent damage leading to microvascular
complications

17. 5-Resistin
• Resistin is a member of a cysteine-rich protein termed as
resistin like molecule (RELM) and circulates as a hexamer
and trimer.
• Hexameric form of this adipokine is more abundant, while
trimeric form induces severe insulin resistance
• The mechanism by which resistin causes the insulin
resistance includes the activation of suppressor of cytokine
signalling-3 (SOCS-3), which attenuates insulin-arbitrate
signalling in adipocytes
• In association with the toll-like receptor (TLR- 4), resistin
stimulates insulin resistance in different cells.
Adipose tissue-specific secretory factor (ADSF)

18. Resistin in metabolism, inflammation, and disease
The FEBS Journal, Volume: 287, Issue: 15, Pages: 3141-3149, First published: 07 April
2020, DOI: (10.1111/febs.15322)

19. 6- Lipocalin-2 (Lcn2)
Neutrophil gelatinase associated lipocalin (NGAL)
• Lcn2 is highly expressed in adipocytes, liver, kidney and on
macrophages and regulates apoptosis and innate immunity
• The primary mechanism underlines the effect of Lcn2 on
insulin resistance include the modulation of 12-
lipoxygenase activity and TNF-á levels in adipose tissue
• Study on LCN2 showed increased hepatic
gluconeogenesis, debilitate lipid metabolism, impaired
oxidation capacity of mitochondria, elevated inflammation
favouring dyslipidemia due to diet-induced obesity, fatty
liver disorders and insulin resistance.
• Overexpression of this adipokine in adipose tissue has
been reported for elevated fat mass, glucose intolerance
and insulin resistance only in females via mitochondrial
dysregulation
Chella Krishnan K, Sabir S, Shum M, et al. Sex-specific metabolic functions of
adipose Lipocalin-2. Mol Metab. 2019; 30:30-47.

20. Lipocalin 2 (LCN2) in organ damage
Lipocalin 2 (LCN2) Expression in Hepatic Malfunction and Therapy. September 2016.Frontiers in
Physiology 7(33)

21. 7- Retinol Binding Protein-4 (RBP-4)
 Higher expression of this adipokine in the adipocyte is
inversely associated with the GLUT-4 expression in the
adipocyte
 Thus, decreased GLUT-4 in adipocytes promotes higher
expression of RBP-4, which inhibits insulin-mediated
insulin receptor substrate-1 (IRS-1) phosphorylation that
can contribute to insulin resistance
 During obesity, RBP-4 is preferentially produced by
visceral fat depot than subcutaneous fat depot, suggesting
the role of intra-abdominal adipose tissue in insulin
resistance .

22. Retinol binding protein-4 links insulin resistance and heart failure
The Associations between Retinol Binding Protein-4 and Cardiometabolic Profile:
Intertwined-Intricate Relationship June 2020 Biomedical and Biotechnology Research
Journal (BBRJ) 4(2)

23. 8-Chemerin
 Chemerin is a pro-inflammatory adipokine predominantly
produced by white adipose tissue (WAT) that regulates the
immune system (adaptive and innate), adipogenesis and
metabolic homeostasis
 Overexpression of chemerin in adipose tissue causes
insulin resistance in human skeletal muscles by modulating
IRS-1, glucose uptake, glycogen synthase kinase 3
phosphorylation (GSK3P)
 Non-alcoholic fatty liver disease (NAFLD) is a common
phenomenon in obesity, which is closely associated with
chemerin induced increased insulin resistance

24. Christa Buechler et al . Chemerin Isoforms and Activity in Obesity. Int. J. Mol.
Sci. 2019, 20(5)
Effect of chemerin on the metabolic status of different organs

25. 9-TNF-á
 TNF-á adipocytokine induces insulin
resistance via decreasing the tyrosine
kinase activity of the insulin receptor
 This causes altered signalling
pathways that can induce insulin
resistance and related diseases

26. Tumor Necrosis Factor‐Alpha: Role in Development of Insulin
Resistance and Pathogenesis of Type 2 Diabetes Mellitus
J of Cellular Biochemistry, Volume: 119, Issue: 1, Pages: 105-110, First published: 01
June 2017, DOI: (10.1002/jcb.26174)
c-Jun N-terminal kinase IκB kinase
Insulin receptor substrate-1

27. an HY, Tan SL, et al . 2020. Development of a novel in vitro insulin resistance
model in primary human tenocytes for diabetic tendinopathy esearch.
Tumor Necrosis Factor‐Alpha: Role in Development
of Insulin Resistance

28. 10- IL-6
 Interleukin-6 is a pro-inflammatory cytokine
secreted by many different cell types and tissues,
including adipose tissue, and plays a significant
role in the immune response.
 This adipocytokine contributes to low-grade
chronic inflammatory state responsible for adipose
tissue dysfunction .
 The mechanism of action by which this cytokine
imparts its role in insulin resistance involves
inhibitory effects on the gene transcription of
PPAR gamma, GLUT-4 and IRS-1.

29. The balance between pro-inflammatory adipokines
and protective adipokines is disturbed in type 2
diabetes
Adipose tissue dysfunction

30. Schematic diagram representing the role of adipokines in insulin
resistance and related diseases

31. CONCLUSION
 Dysfunctional adipose tissue secretes altered levels
of adipokines that are associated with many health
problems, including insulin resistance.
 Recent findings exhibit the role of adipokine
induced insulin resistance as a major risk factor for
the development of chronic diseases like
neurodegenerative diseases, non-alcoholic fatty
liver disease, chronic kidney diseases,
cardiovascular diseases etc.
 However, determining the role of adipokines in the
aetiology of insulin resistance may provide new
opportunities for developing novel therapeutics for
obesity arbitrates insulin resistance.

32. Questions or Comments
Prof. Moustafa Rizk