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	Figure 1. Adiponectin protein structure. Human adiponectin consists of 244 amino acids and mouse adiponectin consists of 247 amino acids. Adiponectin is composed of an N‐terminal signal sequence, a nonhomologous or hypervariable region, a collagenous domain, and a C1q‐like globular domain. Cys‐39/36 (mouse/human) is required for multimer formation.
	Figure 2. Adiponectin multimer formation. In the endoplasmic reticulum, monomeric adiponectin is first hydroxylated and glycosylated on conserved lysine residues in the collagenous domain. Monomers form trimers through initial globular head attractions, which are stabilized by interactions in the collagenous domain. Trimers (LMW) form hexamers (MMW) through disulfide bond formation between single cysteine residues in the N‐terminal hypervariable region. Hexameric adiponectin is converted to larger multimers of 12 to 18 monomers by additional disulfide bonding in the same region.
	Figure 3. Adiponectin receptor signaling. Adiponectin receptor signaling stimulates AMPK, extracellular calcium influx, and PPARα, which are involved in glucose and lipid metabolism. APPL1, which interacts with AdipoR1 or R2, mediates the downstream effects of AMPK activation, by promoting the translocation of LKB1 from the nucleus to the cytosol. In addition, APPL1 potentiates crosstalk between the insulin and adiponectin signaling pathways, by promoting the interaction of IRS1/2 and the insulin receptor. AdipoR1 and R2 are also associated with ceramidase activity, which enhances insulin sensitivity and other pleiotropic effects of adiponectin by binding and converting ceramide to sphingosine‐1‐phophate (S1P). It is important to note that activation of downstream signaling pathways is dependent on cell type and metabolic environment.
	Figure 4. Adiponectin increases insulin sensitivity. In insulin resistance, tissues do not respond adequately to insulin stimulating, resulting in hyperlipidemia, dyslipidemia, hyperglycemia, inflammation, and decreased plasma adiponectin concentrations. Increasing plasma adiponectin concentrations reverses the sequelae of insulin resistance in liver (decrease gluconeogenesis and triglycerides), skeletal muscle (increase fatty acid oxidation and glucose uptake, decreased triglycerides), adipose tissue (stimulate fat storage in small subcutaneous adipocytes), pancreatic beta cells (increase glucose‐stimulated insulin secretion and beta cell protection), endothelial cells (increase eNOS activity and decrease oxidative stress), and various other tissues including macrophages.
	Figure 5. Adiponectin possesses anti‐inflammatory properties. Adiponectin decreases inflammation by targeting differentiation and function of macrophages. Adiponectin inhibits differentiation of myeloid progenitor cells into monocytes, inhibits formation of foam cells from macrophages, promotes the polarization of macrophages to an M2 anti‐inflammatory state, and decreases the expression of TLR4 in macrophages and progenitor cells.
	Figure 6. Adiponectin protects the vasculature. Adiponectin provides vascular protection by various actions including anti‐inflammatory effects, increasing nitric oxide (NO) production, suppressing endothelial activation, inhibiting adhesion molecules (VCAM 1, ICAM 1, E‐selection), inhibiting foam cell formation, inhibiting smooth muscle migration/proliferation, and plaque stabilization. T‐cadherin promotes the accumulation of adiponectin in both endothelial cells and smooth muscle cells.
	Figure 7. Adiponectin is a cardioprotectant. Adiponectin (systemic and locally produced) plays a significant role in protecting the heart against various pathological insults. (A) Hypertrophy: Adiponectin increases AMPK phosphorylation in cardiomyocytes, resulting in an inhibition of prohypertrophic responses, increased eukaryotic elongation factor‐2 (eEF‐2), and increased glucose and fatty acid uptake, which influence cardiac remodeling. (B) Ischemic postconditioning: Adiponectin utilizes AMPK, STAT‐3, and COX‐2 to mediate various cardioprotective effects against apoptosis, inflammation, and oxidative stress. T‐cadherin facilitates binding of adiponectin to AdipoR1 and R2, but is not capable of direct intracellular signaling.
	Figure 8. Adiponectin and colon homeostasis and protection. Dextran sodium sulfate (DSS)‐induced colonic injury is characterized by decreased colon length, decreased epithelial cell proliferation, increased epithelial cell apoptosis, increased proinflammatory cytokine expression and infiltration, and decreased in goblet cell (which secrete protective mucin). All aspects of this colon injury are dramatically increased in mice lacking adiponectin. Adiponectin protects mice from DSS‐injury by increasing intestinal epithelial cell proliferation, decreasing inflammation, preventing goblet cell apoptosis, and stimulating the differentiation of epithelial cells into goblet cells.
	Figure 9. Adiponectin regulation of food intake. Fasting increases serum and CSF adiponectin and AdipoR1 expression in the arcuate nucleus (ARH) of the hypothalamus. Adiponectin activates AMPK in the brain, leading to an increase in neuropeptide Y, feeding and a decrease in energy expenditure. Feeding decreases serum and CSF adiponectin and AdipoR1 expression, leading to a decrease in food intake.
	Figure 10. Adiponectin inhibits fibrosis. Fibrosis is the accumulation of excessive ECMs. Adiponectin inhibits fibrosis in the liver, skin, heart, lung, and kidney. (A) Liver: Activated hepatic stellate cells (HSCs) and Kupffer cells play primary roles in fibrosis development. Adiponectin inhibits Kupffer cell TLR4 signaling, while also promoting macrophage polarization to an M2 (anti‐inflammatory) state. Adiponectin also acts directly on the HSCs, decreasing polarization, migration, collagen/ECM deposition, focal adhesion assembly and MMP‐1, while increasing HSC susceptibility to apoptosis and increasing TIMP‐1 concentrations. (B) Skin: Local and systemic adiponectin inhibits profibrotic TGF‐β signaling at the fibroblast by increasing AMPK and inhibiting canonical Wnt signaling.

Teaching Material

H. Fang, R. L. Judd. Adiponectin Regulation and Function. Compr Physiol 8: 2018, 1031-1063.

Didactic Synopsis

Major Teaching Points:

This article summarizes the current research on adiponectin as a pleiotropic adipokine which regulates numerous physiological functions.

• Adiponectin, a close homolog of the complement 1q (C1q) family, is a 30-kDa monomeric glycoprotein, composed of an N-terminal signal sequence, a nonhomologous or hypervariable region, a collagenous domain, and a C-terminal C1q-like globular domain.
• Adiponectin is an adipocyte-specific factor, with the monomeric protein posttranslationally modified into different multimers (low molecular weight or trimer, middle molecular weight or hexamer, and high molecular weight).
• Plasma adiponectin concentrations are high compared to other hormones, constituting approximately 0.01% to 0.05% of total serum proteins. Studies have correlated various disease states, including obesity, diabetes, and atherosclerosis, with lower adiponectin concentrations.
• AdipoR1 and AdipoR2 are cognate receptors for adiponectin. They are structurally opposite all-known G-protein-coupled receptors, with the N-terminus on the internal surface and the C-terminus on the external surface. T-cadherin receptor plays a role in binding adiponectin in close proximity to AdipoR1 and AdipoR2, but does not have a transmembrane or intracellular domain required for adiponectin signaling.
• A primary physiological function of adiponectin is to increase insulin sensitivity, with decreased plasma concentrations associated with insulin resistance.
• Adiponectin is also a classic antiinflammatory agent, reducing inflammation by inhibiting macrophage differentiation, switching the macrophage phenotype to an antiinflammatory state, and decreasing expression of Toll-like receptor 4. Adiponectin's antiinflammatory ability results in protection of the vasculature, heart, lung, and colon.
• In addition to its antiinflammatory properties, adiponectin directly defends the heart, vasculature, kidney, and colon during periods of stress and injury. Adiponectin also possesses profound antifibrotic properties, inhibiting fibrosis in both liver and skin during injury and disease.
• Drugs which mimic the physiological functions of adiponectin at various target tissues are currently under development.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Adiponectin protein structure. Teaching points: Adiponectin, a close homolog of the complement 1q (C1q) family, is a 30-kDa monomeric glycoprotein. Human adiponectin consists of 244 amino acids and mouse adiponectin consists of 247 amino acids. Adiponectin is composed of an N-terminal signal sequence, a nonhomologous or hypervariable region, a collagenous domain containing 22 collagen repeats and a C-terminal C1q-like globular domain. The single cysteine residue (Cys-39/36; mouse/human) is critical for the formation of the multimeric species of adiponectin through disulfide bonding of trimers. Globular domain is similar in structure to other proteins, including C1q and TNF-α.

Figure 2 Adiponectin multimer formation. Teaching points: The assembly of adiponectin multimers occurs through a complex series of steps in the endoplasmic reticulum (ER). Monomeric adiponectin is first hydroxylated and glycosylated on conserved lysine residues in the collagenous domain. Monomers then form trimers through hydrophobic interactions with the globular heads, which are stabilized by noncovalent interactions within the collagenous domains. Trimeric adiponectin is retained in the ER by the ER-resident chaperone ERp44. This retention allows trimers (low molecular weight adiponectin-LMW) to form hexamers (medium molecular weight adiponectin-MMW) through disulfide bond formation between single cysteine residues in the N-terminal hypervariable region. Hexameric adiponectin is converted to larger multimers of 12 to 18 monomers by additional disulfide bonding in the same region.

Figure 3 Adiponectin receptor signaling. Teaching points: Adiponectin produces its physiological actions by binding to two receptors, identified at AdipoR1 and AdipoR2. AdipoR1 and R2 are ubiquitously expressed, but AdipoR1 is more highly expressed in skeletal muscle and AdipoR2 is mostly restricted to the liver. Adiponectin receptor signaling stimulates AMPK, extracellular calcium influx, and PPARα, which are involved in glucose and lipid metabolism. An adaptor protein (APPL1), which interacts with AdipoR1 or R2, mediates the downstream effects of adenosine monophosphate-activated protein kinase (AMPK) activation, by promoting the translocation of liver kinase B1 (LKB1) from the nucleus to the cytosol. In addition, APPL1 potentiates crosstalk between the insulin and adiponectin signaling pathways, by promoting the interaction of IRS1/2 and the insulin receptor. AdipoR1 and R2 are also associated with ceramidase activity, which enhances insulin sensitivity and other pleiotropic effects of adiponectin by binding and converting ceramides to sphingosine-1-phophate (S1P). It is important to note that activation of downstream signaling pathways is dependent on cell type and metabolic environment.

Figure 4 Adiponectin increases insulin sensitivity. Teaching points: Insulin resistance is the impaired cellular response to insulin, and is clinically characterized by hyperinsulinemia, dyslipidemia, hyperglycemia, inflammation, and decreased plasma adiponectin concentrations. There is a large amount of basic and clinical evidence establishing the important role of adiponectin as an insulin-sensitizing hormone. Increasing plasma adiponectin concentrations reverses the sequelae of insulin resistance in liver (decrease gluconeogenesis and triglycerides), skeletal muscle (increase fatty acid oxidation and glucose uptake, decreased triglycerides), adipose tissue (stimulate fat storage in small subcutaneous adipocytes), pancreatic beta cells (increase glucose-stimulated insulin secretion and beta cell protection), endothelial cells (increase eNOS activity and decrease oxidative stress), and various other tissues including macrophages.

Figure 5 Adiponectin possesses anti-inflammatory properties. Teaching points: A large number of rodent and human studies have demonstrated that adiponectin has anti-inflammatory properties in various disease states, including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease. Adiponectin primarily decreases inflammation by targeting differentiation and function of macrophages. Adiponectin inhibits differentiation of myeloid progenitor cells into monocytes, inhibits formation of foam cells from macrophages, promotes the polarization of macrophages to an M2 anti-inflammatory state, and decreases the expression of TLR4 in macrophages and progenitor cells. Adiponectin can also produce anti-inflammatory effects in endothelial cells, cardiomyocytes, and fibroblasts. Activation of ceramidase, with subsequent reductions in proinflammatory ceramides and increase in anti-inflammatory S1P, can contribute significantly to the anti-inflammatory effects of adiponectin.

Figure 6 Adiponectin protects the vasculature. Teaching points: Adiponectin plays an important role in protecting the vasculature when the endothelial barrier is damaged. Adiponectin accumulates in vascular walls where it provides protection by various actions including antiinflammatory effects, increasing nitric oxide (NO) production, suppressing endothelial activation, inhibiting adhesion molecules (VCAM 1, ICAM 1, E-selection), inhibiting foam cell formation, inhibiting smooth muscle migration/proliferation and plaque stabilization. AdipoR1, R1, and APPL1 all play critical roles in adiponectin's ability to protect and repair the vasculature. T-cadherin receptors also play an important role in the vasculoprotective and anti-atherosclerotic effects of adiponectin. In the vasculature, T-cadherin receptors promote the accumulation of adiponectin in both endothelial cells and smooth muscle cells. In addition to protecting the vasculature from damage, adiponectin also plays an important role in vascular repair, in part by stimulating the formation of new blood vessels.

Figure 7 Adiponectin is a cardioprotectant. Teaching points: Adiponectin (systemic and locally produced) plays a significant role in protecting the heart against various pathological insults. Clinical and epidemiological studies have correlated low adiponectin concentrations with the development of coronary artery disease, myocardial infarction, hypertension, left ventricular hypertrophy, and other cardiovascular dysfunctions. As with vascular injury and atherosclerosis, adiponectin protects the heart by attenuating inflammation and shielding the heart from damage induced by a multitude of mediators. Adiponectin also directly defends the heart during periods of stress and injury. (A) In cardiac hypertrophy, adiponectin increases AMPK phosphorylation in cardiomyocytes, resulting in an inhibition of prohypertrophic responses, increased eukaryotic elongation factor-2 (eEF-2), and increased glucose and fatty acid uptake, which influence cardiac remodeling. The AMPK-mediated antihypertrophic effects of adiponectin are produced through AdipoR1 and R2, which are expressed by cardiac myocytes and heart tissue. (B) In acute myocardial ischemia-reperfusion injury associated with cardiac damage, adiponectin protects the heart by stimulating AMPK, signal transducer and activator of transcription 3 (STAT-3), and cyclooxygenase-2 (COX-2) to mediate various cardioprotective effects against apoptosis, inflammation, and oxidative stress. T-cadherin facilitates binding of adiponectin to AdipoR1 and R2, but is not capable of direct intracellular signaling.

Figure 8 Adiponectin and colon homeostasis and protection. Teaching points: The intestinal epithelial layer plays a critical role in colon homeostasis by serving as a protective barrier against undigested intestinal contents and bacteria in the gut. Dextran sodium sulfate (DSS) induced colonic injury is characterized by increased colon length, decreased epithelial cell proliferation, increased epithelial cell apoptosis, increased proinflammatory cytokine expression and infiltration, and decreased in goblet cell (which secrete protective mucin). All aspects of this colon injury are dramatically increased in mice lacking adiponectin. Adiponectin protects mice from DSS-injury by increasing intestinal epithelial cell proliferation, decreasing inflammation, preventing goblet cell apoptosis, and stimulating the differentiation of epithelial cells into goblet cells. AdipoR1 is required for adiponectin-mediated protection against cellular stress and apoptosis in the colon.

Figure 9 Adiponectin regulation of food intake. Teaching points: Adiponectin is known as a starvation hormone, because serum concentrations increase during fasting. Trimeric and hexameric adiponectin are transported from the peripheral circulation into the cerebrospinal fluid (CSF), where they cross the blood-brain barrier and interact with AdipoR1 in the arcuate nucleus (ARH) of the hypothalamus. HMW multimers of adiponectin are excluded from transportation across the blood-brain barrier due to their molecular weight. Adiponectin signaling in the ARH activates AMPK, leading to an increase in neuropeptide Y, which stimulates food intake and suppresses energy expenditure. Feeding decreases serum and CSF adiponectin and AdipoR1 expression, leading to a decrease in food intake.

Figure 10 Adiponectin inhibits fibrosis. Teaching points: Fibrosis is the result of an accumulation of excessive extracellular matrix proteins (ECMs). Adiponectin possesses profound antifibrotic properties. Adiponectin inhibits fibrosis in the liver, skin, heart, lung, and kidney. (A) In the liver, activated hepatic stellate cells (HSCs) and Kupffer cells play primary roles in fibrosis development by secreting collagen and other ECMs and releasing chemotactic factors. Adiponectin inhibits fibrosis by regulating the activity of the HSCs and decreasing inflammation. Specifically, adiponectin inhibits Kupffer cell Toll-like receptor 4 (TLR4) signaling, while also promoting macrophage polarization to an M2 (antiinflammatory) state. Adiponectin also acts directly on the HSCs, decreasing polarization, migration, collagen/ECM deposition, focal adhesion assembly, and matrix metalloproteinase (MMP-1), while increasing HSC susceptibility to apoptosis and increasing TIMP-1 concentrations. Adiponectin also plays a role in recovery from liver injury, by regulating hepatocyte proliferation. (B) Dermal adipose tissue plays an important role in the skin, including wound healing, insulation and protection against microbes. Decreased adiponectin is associated with changes in skin architecture and fibrosis. Adiponectin receptor stimulation in dermal fibroblasts activates AMPK, blocking transforming growth factor beta (TGF-β)/Smad signaling and profibrotic gene expression.