Nutrient sensing and inflammation in metabolic diseases

Key Points

  • Mounting an immune response is a metabolically costly endeavour and cannot operate well under conditions of energy deficit. Energy surplus (for example, in individuals that are obese or suffer from metabolic syndrome) can also impair immune responses and induce chronic inflammation. The integrated and proper functioning of each system is paramount to the health of the other.

  • Chronic inflammation, particularly when it occurs in metabolically important organs such as the liver and adipose tissue, has a crucial role in the emergence of many chronic metabolic diseases, including diabetes, fatty liver disease and cardiovascular disease. It is important to recognize that this is not a response that resembles classic inflammation and perhaps could be considered as an aberrant form of immunity that is triggered by nutrients or other intrinsic cues.

  • During most conditions of stress and inflammation, changes in metabolism occur, and insulin signalling is impaired through protein modifications, such as serine phosphorylation of insulin-receptor substrate proteins. These modifications resemble the events that occur during conditions of obesity, insulin resistance and type 2 diabetes. Nutrient overload and/or lack of protection from the inflammatory response lead to deterioration of metabolic health.

  • Recent studies have given rise to the concept that metabolic stress might be sensed by organelles, particularly the endoplasmic reticulum (ER) and mitochondria, and the resulting organelle dysfunction could trigger a network of stress signalling that could disrupt metabolic homeostasis. The ER can also serve as a convergence point of nutrient and pathogen responses.

  • Intriguingly, many of the nutrient-sensing pathways are subverted by pathogens for their proliferation and survival, and revisiting some of these links may provide a basis for the emergence of metabolic diseases and present new platforms for research in the fields of metabolism and infection.

Abstract

The proper functioning of the pathways that are involved in the sensing and management of nutrients is central to metabolic homeostasis and is therefore among the most fundamental requirements for survival. Metabolic systems are integrated with pathogen-sensing and immune responses, and these pathways are evolutionarily conserved. This close functional and molecular integration of the immune and metabolic systems is emerging as a crucial homeostatic mechanism, the dysfunction of which underlies many chronic metabolic diseases, including type 2 diabetes and atherosclerosis. In this Review we provide an overview of several important networks that sense and manage nutrients and discuss how they integrate with immune and inflammatory pathways to influence the physiological and pathological metabolic states in the body.

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Figure 1: Molecular characteristics shared between adipocytes and macrophages in physiological conditions and metabolic disease states.
Figure 2: Nutrient sensing and inflammation.
Figure 3: The unfolded-protein response, nutrient sensing and inflammation.
Figure 4: The mammalian target of rapamycin pathway, amino-acid sensing and inflammation.
Figure 5: Lipid-sensing pathways and inflammation.

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Acknowledgements

This work is supported in part by grants from National Institutes of Health (DK52539, DK64360, HL65405), and American Diabetes Association (I03RA41) to G.S.H. E.E. is supported by a Ruth Kirschstein National Research Award. We thank the members of the Hotamisligil laboratory for discussions, comments and research contributions that lead to maturation of this review. We are especially grateful to A. Onur for help with the figures, S. Hummasti for discussion and editing, H. Xu for assistance with analysis of microarray data and R. Foote for technical assistance with the manuscript. We regret that we could not cite or review the scientific contributions of many others owing to space limitations.

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Correspondence to Gökhan S. Hotamisligil.

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Dr. Hotamisligil is the founder of Syndexa Pharmaceuticals and is on its scientific advisory board. He is also on the scientific advisory board of Lipomics, Inc. Dr. Hotamisligil receives research funding from Syndexa Pharmaceuticals.

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Glossary

Sepsis

A systemic response to severe bacterial infections that are generally caused by Gram-negative bacterial endotoxins. Sepsis induces a hyperactive and out-of-balance network of pro-inflammatory cytokines, affecting vascular permeability, cardiac function and metabolic balance, and ultimately leads to tissue necrosis, multiple-organ failure and death.

Metabolic syndrome

A cluster of conditions, such as hypertension, hyperinsulinaemia, hypercholesteraemia and abdominal obesity, that occur together, increasing the risk of heart disease, stroke and diabetes.

Adipose tissue

Connective tissue with a network of blood vessels in which fat is stored and the cells are distended by droplets of fat.

Foam cells

Macrophages that localize to sites of early-stage inflammation in the vessel wall, which subsequently ingest oxidized low-density lipoprotein and slowly become overloaded with lipids. They are called foam cells because they have numerous cytoplasmic vesicles that contain cholesterol and other lipids. Foam cells eventually die and attract more macrophages, and further propagate inflammation in the vessel wall.

Atherosclerosis

A chronic disorder of the arterial wall that is characterized by damage to the endothelium, which gradually induces deposits of cholesterol, cellular debris, calcium and other substances and ultimately triggers local inflammation. These deposits finally lead to plaque formation and arterial stiffness.

Anabolic hormone

A hormone that is involved in the synthesis of macromolecules from simpler intermediates.

Insulin resistance

The reduced sensitivity of the body's insulin-dependent processes (such as glucose uptake and lipolysis) to insulin. Insulin resistance is typical of type 2 diabetes but often occurs in the absence of diabetes.

Mammalian target of rapamycin

(mTOR). A conserved serine/threonine protein kinase that regulates cell growth and metabolism, as well as cytokine and growth-factor expression, in response to environmental cues. mTOR receives stimulatory signals from RAS and phosphoinositide 3-kinase downstream of growth factors and nutrients, such as amino acids, glucose and oxygen.

Peroxisome-proliferator-activated receptors

Nuclear receptors that participate in the regulation of cellular metabolism and differentiation.

Unfolded-protein response

An adaptive response that increases the ability of the endoplasmic reticulum to fold and translocate proteins, decreases the synthesis of proteins, coordinates stress and antioxidant responses, and can result in the arrest of the cell cycle and apoptosis.

Chaperone protein

A protein that assists the folding of newly synthesized proteins into a particular three-dimensional conformation by binding and stabilizing folding intermediates.

Acute-phase proteins

A group of proteins, including Creactive protein, serum amyloid A, fibrinogen and α1-acid glycoprotein, that are secreted into the blood in increased or decreased quantities by hepatocytes in response to trauma, inflammation or disease. These proteins can be inhibitors or mediators of inflammatory processes.

Plasma cells

Terminally differentiated quiescent B cells that develop from plasmablasts and are characterized by their capacity to secrete large amounts of antibodies.

Atherosclerotic plaque

A lesion that consists of a fibrotic cap surrounding a lipid-rich core. The lesion is the site of inflammation, lipid accumulation and cell death.

Leptin resistance

Reduced sensitivity to the effects of leptin, which is a hormone that is produced by fat cells and has a key role in regulating energy intake and energy expenditure.

Rapamycin

An immunosuppressive drug that, in contrast to calcineurin inhibitors, does not prevent T-cell activation but blocks interleukin-2-mediated clonal expansion by blocking mTOR.

Myeloid-derived suppressor cells

(MDSCs). A population of cells that consists of mature and immature myeloid cells. MDSCs are generated and/or activated during an inflammatory immune response and negatively affect T cells through direct interactions and secreted components, which leads to the impairment of T-cell function.

Essential amino acid

An amino acid that cannot be synthesized by cells and must be obtained through the diet.

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Hotamisligil, G., Erbay, E. Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol 8, 923–934 (2008). https://doi.org/10.1038/nri2449

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