Lipid-induced Insulin Resistance

Obesity is a well-established risk factor for the development of insulin resistance. Obesity is associated with the increased deposition of lipids in non-adipose tissue with subsequent decreases in insulin sensitivity. Currently, the mechanisms by which increased fat accumulation leads to insulin resistance and metabolic syndrome are not completely understood.

Obesity may set up a state of inflammation in the body leading to increased production of inflammatory cytokines that negatively impact insulin sensitivity. This theory is consistent with studies showing elevated levels of the proinflammatory cytokines IL-6 and TNF-α in individuals with insulin resistance and type 2 diabetes. Alternatively, hormone production by adipose tissue may be dysregulated leading to the increased production of adipokines that cause insulin resistance.

A third theory examines the capacity of adipose tissue to store lipids. This theory postulates that an individual's capacity to store lipids in adipose tissue has a set maximal limit. When this limit is exceeded, excess lipids spill over into plasma resulting in elevated plasma free fatty acid and triglyceride levels. This results in the increased import and storage of these molecules in non-adipose tissues such as skeletal muscle and liver. The ectopic storage of lipids in non-adipose tissues may result in metabolic derangements via lipid-induced toxicity (lipotoxicity). Lipotoxicity may also contribute to the loss of pancreatic β cells that occurs during the development of type 2 diabetes.

The lipotoxicity hypothesis is supported by studies in which cells are cultured with an excess of long-chain saturated fatty acids complexed to serum albumin. In these studies, apoptosis is induced in a dosedependent manner and is enhanced by high-glucose treatment. Further evidence for the lipotoxicity theory comes from the study of lipidystrophy patients who have generalized or partial loss of adipose tissue. These individuals with reduced lipid storage capacity often present with severe insulin resistance, dyslipidaemia, and fatty liver.

The adipose expandability hypothesis of obesity-induced insulin resistance postulates that adipose tissue has a limited maximal capacity to store lipids. When this limit is reached, excess fatty acids spill over into the blood leading to their ectopic storage in skeletal muscle and hepatocytes. This ectopic storage results in lipotoxicity and insulin resistance.

Free Fatty Acids and Associated Reagents
Name	Description	Catalog No.
Albumin from bovine serum	–	A8806-1G A8806-5G
Albumin human	Albumins are soluble monomeric proteins found in the body fluids and tissues of animals and in some plant seeds. Serum albumin functions as a carrier protein for steroids, fatty acids, and thyroid hormones. Serum albumins are also vital in regulating the colloidal osmotic pressures of blood.	A9731-1G A9731-5G A9731-10G
Albumin from human serum	Albumins are soluble monomeric proteins found in the body fluids and tissues of animals and in some plant seeds. Serum albumin functions as a carrier protein for steroids, fatty acids, and thyroid hormones. Serum albumins are also vital in regulating the colloidal osmotic pressures of blood.	A3782-100MG A3782-500MG A3782-1G A3782-5G A3782-10G
Arachidic acid	Arachidic acid is a saturated fatty acid with a 20 carbon chain. Arachidic acid occurs naturally in fish and vegetable oils. Diets rich in saturated fats like arachidic acid are associated with increased levels of serum low density lipoproteins.	A3631-500MG A3631-1G A3631-5G A3631-10G A3631-25G
Arachidonic acid	Arachidonic acid and its metabolites play important roles in a variety of biological processes, including signal transduction, smooth muscle contraction, chemotaxis, cell proliferation and differentiation, and apoptosis.	A3555-10MG A3555-50MG A3555-100MG A3555-1G
1,2-Dipalmitoyl-sn-glycero-3-phosphate sodium salt	–	P4013-25MG P4013-100MG
cis-4,7,10,13,16,19-Docosahexaenoic acid	Docosahexaenoic acid, DHA, is an omega-3 polyunsaturated fatty acid with 22 carbons and six double bonds, the first double bond occuring at position three from the methyl terminus (22:6 n-3). DHA is a component of lipid membranes and the myelin sheath. DHA also serves as a precursor for signaling molecules such as prostaglandins and eicosanoids.	D2534-25MG D2534-100MG D2534-1G
Linoleic acid	Fatty acid that is typically bound to a carrier molecule such as BSA or cyclodextrin for use in cell culture.	L1012-100MG L1012-1G L1012-5G
Linolenic acid	–	L2376-500MG L2376-5G L2376-10G
Myristic acid	Myristic acid is a straight-chain 14-carbon fatty acid. Diets rich in myristic acid, along with lauric and palmitic acids, are associated with increased serum levels of low densisity lipoprotein cholesterol.	M3128-10G M3128-100G M3128-500G
Oleic acid	Activates protein kinase C in hepatocytes. Uncouples oxidative phosphorylation. Inhibits 2,4-dinitrophenol-stimulated ATPase. Action reversed by adding serum albumin.	O1383-1G O1383-5G O1383-25G
Palmitic acid	Palmitic acid is a straight-chain 16-carbon fatty acid. Diets rich in palmitic acid, along with lauric and myristic acids, are associated with increased serum levels of low-density lipoprotein cholesterol. Palmitic acid is the first fatty acid produced by lipogenesis. It is a negative regulator of acetyl-CoA carboxylase (ACC) and is implicated in fatty acid-induced insulin resistance.	P5585-10G P5585-25G P5585-100G
Palmitoleic acid	Palmitoleic acid is a 16-carbon, omega-7, monounsaturated fatty acid that is enriched in the triglycerides of human adipose tissue and in liver.	P9417-100MG P9417-1G P9417-5G
Stearic acid	–	S4751-1G S4751-5G S4751-10G S4751-25G S4751-100G

Hormones, Cytokines, and Adipokines Involved in Insulin Resistance

Adipose tissue is an endocrine organ that secretes multiple hormones, cytokines, and adipokines. These bioactive peptides and proteins can influence multiple metabolic processes, including insulin sensitivity.

Name	Structure Description	Catalog No.
Adiponectin human	Adiponectin (also called Acrp30, AdipoQ) is an adipocyte specific secreted protein that circulates in the plasma. It is induced during adipocyte differentiation and it secretion is stimulated by insulin. Human adiponectin shares about 83% amino acid identity with that of mouse and about 90% with that of rat. Adiponectin plays a role in various physiological processes such as energy homeostasis and obesity. Plasma levels of adiponectin are reduced in obese humans, and decreased levels are associated with insulin resistance and hyperinsulinemia.	SRP4901-25UG
Adiponectin from mouse	Adiponectin (also called Acrp30, AdipoQ) is an adipocyte specific secreted protein that circulates in the plasma. It is induced during adipocyte differentiation and it secretion is stimulated by insulin. Human adiponectin shares about 83% amino acid identity with that of mouse and about 90% with that of rat. Adiponectin plays a role in various physiological processes such as energy homeostasis and obesity. Plasma levels of adiponectin are reduced in obese humans, and decreased levels are associated with insulin resistance and hyperinsulinemia.	SRP4902-25UG
Adiponectin from rat	Adiponectin (also called Acrp30, AdipoQ) is an adipocyte specific secreted protein that circulates in the plasma. It is induced during adipocyte differentiation and it secretion is stimulated by insulin. Human adiponectin shares about 83% amino acid identity with that of mouse and about 90% with that of rat. Adiponectin plays a role in various physiological processes such as energy homeostasis and obesity. Plasma levels of adiponectin are reduced in obese humans, and decreased levels are associated with insulin resistance and hyperinsulinemia.	SRP4903-25UG
Angiotensin II human	Angiotensin II is important in regulating cardiovascular hemodynamics and cardiovascular structure.	A9525-1MG A9525-5X1MG A9525-5MG A9525-10MG A9525-50MG
Angiotensinogen from human plasma	–	A2562-.1MG
Interleukin-6 human	Interleukin-6 is a multifunctional protein originally discovered in the media of cells stimulated with double stranded RNA. IL-6 appears to be directly involved in the responses that occur after infection and injury and may prove to be as important as IL-1 and TNF-α in regulating the acute phase response. IL-6 is reported to be produced by fibroblasts, activated T cells, activated monocytes or macrophages, and endothelial cells. It acts upon a variety of cells, including fibroblasts, myeloid progenitor cells, T cells, B cells and hepatocytes. IL-6 induces multiple effects, as indicated by its numerous synonyms: plasmacytoma growth factor (PCT-GF), interferon-ß-2 (IFN-ß2), monocyte derived human B cell growth factor, B cell stimulating factor (BSF-2), hepatocyte stimulating factor (HSF), Interleukin Hybridoma/ Plasmacytoma-1 (IL-HP1). In addition, IL-6 appears to interact with IL-2 in the proliferation of T lymphocytes. IL-6 also potentiates the proliferative effect of IL-3 on multipotential hematopoietic progenitors.	H7416-10UG
Interleukin-6 from mouse	Interleukin-6 is a multifunctional protein originally discovered in the media of cells stimulated with double stranded RNA. IL-6 appears to be directly involved in the responses that occur after infection and injury and may prove to be as important as IL-1 and TNF-α in regulating the acute phase response. IL-6 is reported to be produced by fibroblasts, activated T cells, activated monocytes or macrophages, and endothelial cells. It acts upon a variety of cells, including fibroblasts, myeloid progenitor cells, T cells, B cells and hepatocytes. IL-6 induces multiple effects, as indicated by its numerous synonyms: plasmacytoma growth factor (PCT-GF), interferon-ß-2 (IFN-ß2), monocyte derived human B cell growth factor, B cell stimulating factor (BSF-2), hepatocyte stimulating factor (HSF), Interleukin Hybridoma/ Plasmacytoma-1 (IL-HP1). In addition, IL-6 appears to interact with IL-2 in the proliferation of T lymphocytes. IL-6 also potentiates the proliferative effect of IL-3 on multipotential hematopoietic progenitors.	I9646-5UG
JE (MCP-1) from mouse	Mouse JE (also known as macrophage/monocyte chemotactic protein) is a 13.8 kDa protein containing 125 amino acid residues. It plays an important role in the inflammatory response of blood monocytes and tissue microphages.	SRP4207-10UG
Leptin human	Hormone produced primarily in adipocytes; primary site of action appears to be on neurons in the hypothalamus that are involved in regulating energy balance, appetite, and body weight.	L4146-1MG
Leptin from mouse	Hormone produced primarily in adipocytes; primary site of action appears to be on neurons in the hypothalamus that are involved in regulating energy balance, appetite, and body weight.	L3772-1MG
Leptin from rat	Hormone produced primarily in adipocytes; primary site of action appears to be on neurons in the hypothalamus that are involved in regulating energy balance, appetite, and body weight.	L5037-1MG
Monocyte Chemotactic Protein-1 human	–	M6667-10UG
Monocyte Chemotactic Protein-1 from rat	–	M208-10UG
Plasminogen activator inhibitor 1 (PAI-1) human	Plasminogen activator inhibitor 1 (PAI-1), a member of the Serpin superfamily of serine protease inhibitors, is involved in extracellular matrix remodeling and implicated in processes like angiogenesis, chemotaxis, ovulation, and embryogenesis.	A8111-25UG
Resistin from mouse	Mouse Resistin is a new member to the family of adipocyte secreted proteins. The biological functions of Resistin as well as its molecular target are largely unknown. Whether it promotes or antagonizes insulin action is still unclear. Recombinant mouse Resistin is a 20.2 kDa dimeric protein consisting of two 94 amino acid polypeptide chains.	SRP4560-25UG
Resistin from rat	Resistin is a new member to the family of adipocyte-secreted proteins. The biological functions of Resistin as well as its molecular target are largely unknown. Whether it promotes or antagonizes insulin action is still unclear. Recombinant rat Resistin is an 11.9 kDa protein consisting of 94 amino acid residues and 16 additional amino acids residues – His Tag.	SRP4561-25UG
Tumor Necrosis Factor-α human	Tumor necrosis factor-α, also known as cachectin, is expressed as a 26 kDa membrane bound protein and is then cleaved by TNF-α converting enzyme (TACE) to release the soluble 17 kDa monomer, which forms homotrimers in circulation. TNF-α plays roles in anti-tumor activity, immune modulation, inflammation, anorexia, cachexia, septic shock, viral replication and hematopoiesis. TNF-α is cytotoxic for many transformed cells, but in normal diploid cells, it stimulates proliferation (fibroblasts), differentiation (myeloid cells) or activation (neutrophils). TNF-α also shows antiviral effects against both DNA and RNA viruses and induces production of several other cytokines.	H8916-10UG
Tumor Necrosis Factor-α from mouse	Tumor necrosis factor-α, also known as cachectin, is expressed as a 26 kDa membrane bound protein and is then cleaved by TNF-α converting enzyme (TACE) to release the soluble 17 kDa monomer, which forms homotrimers in circulation. TNF-α plays roles in anti-tumor activity, immune modulation, inflammation, anorexia, cachexia, septic shock, viral replication and hematopoiesis. TNF-α is cytotoxic for many transformed cells, but in normal diploid cells, it stimulates proliferation (fibroblasts), differentiation (myeloid cells) or activation (neutrophils). TNF-α also shows antiviral effects against both DNA and RNA viruses and induces production of several other cytokines.	T7539-10UG
Visfatin from rat	Tumor necrosis factor-α, also known as cachectin, is expressed as a 26 kDa membrane bound protein and is then cleaved by TNF-α converting enzyme (TACE) to release the soluble 17 kDa monomer, which forms homotrimers in circulation. TNF-α plays roles in anti-tumor activity, immune modulation, inflammation, anorexia, cachexia, septic shock, viral replication and hematopoiesis. TNF-α is cytotoxic for many transformed cells, but in normal diploid cells, it stimulates proliferation (fibroblasts), differentiation (myeloid cells) or activation (neutrophils). TNF-α also shows antiviral effects against both DNA and RNA viruses and induces production of several other cytokines.	SRP4909-10UG
Visfatin human, recombinant from E. coli	Visfatin, also known as pre-B cell colony-enhancing factor, is a cytokine that is highly expressed in visceral fat and was originally isolated as a secreted factor that synergizes with IL-7 and stem cell factors to promote the growth of B cell precursors	68373-10UG

Enzymes Involved in Fatty Acid Release

Insulin resistance in adipose tissue results in a reduction in the uptake of circulating free fatty acids and an increase in the hydrolysis of stored triglycerides by lipases. The net result of these actions is an increase in circulating free fatty acids.

Diets high in saturated fats are associated with an increased risk of developing type 2 diabetes.

Name	Description	Catalog No.
ERK1, active, untagged human	ERK1 is a protein serine/threonine kinase that is a member of the extracellular signal-regulated kinases (ERKs) which are activated in response to numerous growth factors and cytokines.Activation of ERK1 requires both tyrosine and threonine phosphorylation that is mediated by MEK. ERK1 is ubiquitously distributed in tissues with the highest expression in heart, brain and spinal cord. Activated ERK1 translocates into the nucleus where it phosphorylates various transcription factors (e.g., Elk-1, c-Myc, c-Jun, c-Fos, and C/EBP beta).	E7407-10UG
ERK2, active, GST tagged human	ERK2 is a protein serine/threonine kinase that is a member of the extracellular signal-regulated kinases (ERKs) which are activated in response to numerous growth factors and cytokines. Activation of ERK2 requires both tyrosine and threonine phosphorylation that is mediated by MEK. ERK2 is ubiquitously distributed in tissues with the highest expression in heart, brain and spinal cord. Activated ERK2 translocates into the nucleus where it phosphorylates various transcription factors (e.g., Elk-1, c-Myc, c-Jun, c-Fos, and C/EBP beta).	E1283-10UG
Lipase from human pancreas	Tri-, di-, and monoglycerides are hydrolyzed (in decreasing order of rate).	L9780-50UN
Lipase from porcine pancreas	Tri-, di-, and monoglycerides are hydrolyzed (in decreasing order of rate).	L0382-100KU L0382-1MU
Lipase from porcine pancreas	Tri-, di-, and monoglycerides are hydrolyzed (in decreasing order of rate).	L3126-25G L3126-100G L3126-500G
Lipoprotein Lipase from bovine milk	–	L2254-1KU L2254-5KU
Protein Kinase A Catalytic Subunit ß, Active human	cAMP-dependent protein kinase (PKA; EC 2.7.1.37) is an essential enzyme in the signaling pathway of the second messenger cAMP. Through phosphorylation of target proteins, PKA controls many biochemical events in the cell including regulation of metabolism, ion transport, and gene transcription.	P6998-5UG

Kits and Reagents for Measuring Lipids and Fatty Acids

Insulin resistance in adipose tissue results in a reduction in the uptake of circulating free fatty acids and an increase in the hydrolysis of stored triglycerides by lipases. The net result of these actions is an increase in circulating free fatty acids.

Materials

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