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Immunologic and endocrine functions of adipose tissue: implications for kidney disease

Key Points

  • Adipocytes are metabolically active cells; they produce signalling lipids and metabolites and secrete protein factors (adipokines)

  • The relative levels of these lipids, proteins and metabolites change under different nutritional and pathological states, with adipocytes integrating information regarding the metabolic status quo at any given time and adjusting their cellular physiological state to maintain systemic homeostasis

  • Adipocyte-derived factors establish complex paracrine and endocrine signalling axes between local cell types in adipose tissue and other organs, including the kidney

  • A number of adipokines, including leptin and adiponectin, have well-established effects on kidney function; adiponectin might also be produced locally within the kidney and exert important metabolic functions in an autocrine fashion

  • As a source of pro-inflammatory cytokines, adipose tissue might exert important effects on the inflammatory state of the kidney

  • The renin–angiotensin system is present in adipose tissue and mediates inflammation in response to nutritional interventions; activation of this axis triggers profound signalling events in the kidney

Abstract

Excess adiposity can induce adverse sequelae in multiple cell types and organ systems. The transition from the lean to the obese state is characterized by fundamental cellular changes at the level of the adipocyte. These changes affect the local microenvironment within the respective adipose tissue but can also affect nonadipose systems. Adipocytes within fat pads respond to chronic nutrient excess through hyperplasia or hypertrophy, which can differentially affect interorgan crosstalk between various adipose depots and other organs. This crosstalk is dependent on the unique ability of the adipocyte to coordinate metabolic adjustments throughout the body and to integrate responses to maintain metabolic homeostasis. These actions occur through the release of free fatty acids and metabolites during times of energy need — a process that is altered in the obese state. In addition, adipocytes release a wide array of signalling molecules, such as sphingolipids, as well as inflammatory and hormonal factors (adipokines) that are critical for interorgan crosstalk. The interactions of adipose tissue with the kidney — referred to as the adipo–renal axis — are important for normal kidney function as well as the response of the kidney to injury. Here, we discuss the mechanistic basis of this interorgan crosstalk, which clearly has great therapeutic potential given the increasing rates of chronic kidney disease secondary to obesity and type 2 diabetes mellitus.

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Figure 1: Distinct features of adipocytes.
Figure 2: Mechanisms of crosstalk between adipocytes and the kidney.
Figure 3: Angiotensin signalling in adiporenal crosstalk.
Figure 4: Mechanisms of leptin function on kidney injury.
Figure 5: Mechanisms of adiponectin actions in the kidney.

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Acknowledgements

The authors are supported by US National Institutes of Health (NIH) Grants R01-DK086629, R01-DK55758, P01-DK088761 and P01-AG051459 as well as by an unrestricted grant from the NovoNordisk Foundation.

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PowerPoint slides

Glossary

Beiging

A biological process that often occurs under cold stress or β-adrenergic stimulation to increase heat production, during which white adipose tissue switches from a unilocular to a multilocular phenotype (with more beige adipocytes).

M2-like macrophages

So-called alternatively activated macrophages that secrete cytokines that decrease inflammation.

M1-like macrophages

M1-polarized macrophages that release cytokines that encourage inflammation.

Unilocular

White adipocytes that display unilocular features, with a single large lipid droplet in the cytoplasm.

Multilocular

Brown and beige adipocytes that display a multilocular phenotype, with many small lipid droplets in the cytoplasm.

Dominant isoform

The major isoform with the most abundant expression within a protein family.

Acetylation

A type of post-translational histone modification that facilitates or inhibits the binding of a protein complex to its histone-binding site via remodelling of the chromatin structure, resulting in altered gene expression.

Monoubiquitylation

A type of post-translational histone modification; some histones, such as histone 2A, can be monoubiquitylated by adding a ubiquitin unit, thus regulating gene transcription by acting on the chromatin structure.

Leptin resistance

A condition that is often found in obesity and diabetes, in which leptin loses its anorectic functions in the brain despite high circulating levels of the hormone.

Uraemic toxin

Uraemic toxins are a group of uraemic retention solutes found in uraemic syndrome that are otherwise excreted by healthy kidneys.

Berberine

A compound found in herbs that increases adiponectin levels and activates 5′-AMP-activated protein kinase catalytic subunit α-1 (PRKAA1; also known as AMPK) and has anti-inflammatory and antidiabetic properties.

Sphingolipids

A class of lipids that can be part of cellular membranes. Moreover, sphingolipids and their metabolites, such as ceramides, sphingosine and sphingosine-1-phosphate, are signalling molecules and are involved in multiple diseases, including obesity, diabetes, cardiovascular disease, cancer and kidney disease.

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Zhu, Q., Scherer, P. Immunologic and endocrine functions of adipose tissue: implications for kidney disease. Nat Rev Nephrol 14, 105–120 (2018). https://doi.org/10.1038/nrneph.2017.157

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