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Annu Rev Physiol 2022 02;84:1-16

Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA; email:

The role of β-adrenergic receptors (βARs) in adipose tissue to promote lipolysis and the release of fatty acids and nonshivering thermogenesis in brown fat has been studied for so many decades that one would think there is nothing left to discover. With the rediscovery of brown fat in humans and renewed interest in UCP1 and uncoupled mitochondrial respiration, it seems that a review of adipose tissue as an organ, pivotal observations, and the investigators who made them would be instructive to understanding where the field stands now. The discovery of the β-adrenergic receptor was important for accurately defining the pharmacology of the adipocyte, while the clinical targeting of this receptor for obesity and metabolic disease has had its highs and lows. Read More

Annu Rev Physiol 2022 02;84:585-610

INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Paris, France; email:

Mineralocorticoid receptor (MR) activation in the heart and vessels leads to pathological effects, such as excessive extracellular matrix accumulation, oxidative stress, and sustained inflammation. In these organs, the MR is expressed in cardiomyocytes, fibroblasts, endothelial cells, smooth muscle cells, and inflammatory cells. We review the accumulating experimental and clinical evidence that pharmacological MR antagonism has a positive impact on a battery of cardiac and vascular pathological states, including heart failure, myocardial infarction, arrhythmic diseases, atherosclerosis, vascular stiffness, and cardiac and vascular injury linked to metabolic comorbidities and chronic kidney disease. Read More

Annu Rev Physiol 2022 02;84:87-112

Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA; email:

At-risk alcohol use is a major contributor to the global health care burden and leads to preventable deaths and diseases including alcohol addiction, alcoholic liver disease, cardiovascular disease, diabetes, traumatic injuries, gastrointestinal diseases, cancers, and fetal alcohol syndrome. Excessive and frequent alcohol consumption has increasingly been linked to alcohol-associated tissue injury and pathophysiology, which have significant adverse effects on multiple organ systems. Extensive research in animal and in vitro models has elucidated the salient mechanisms involved in alcohol-induced tissue and organ injury. Read More

Annu Rev Physiol 2022 02;84:209-227

Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA; email:

Noncommunicable diseases are chronic diseases that contribute to death worldwide, but these diseases can be prevented and mitigated with regular exercise. Exercise activates signaling molecules and the transcriptional network to promote physiological adaptations, such as fiber type transformation, angiogenesis, and mitochondrial biogenesis. AMP-activated protein kinase (AMPK) is a master regulator that senses the energy state, promotes metabolism for glucose and fatty acid utilization, and mediates beneficial cellular adaptations in many vital tissues and organs. Read More

Annu Rev Physiol 2022 02 29;84:507-531. Epub 2021 Nov 29.

Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA; email:

The kidney maintains electrolyte, water, and acid-base balance, eliminates foreign and waste compounds, regulates blood pressure, and secretes hormones. There are at least 16 different highly specialized epithelial cell types in the mammalian kidney. The number of specialized endothelial cells, immune cells, and interstitial cell types might even be larger. Read More

Annu Rev Physiol 2022 02 15;84:229-255. Epub 2021 Nov 15.

Unit of Cardiac Physiology, Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom; email:

In mammalian cardiac myocytes, the plasma membrane includes the surface sarcolemma but also a network of membrane invaginations called transverse (t-) tubules. These structures carry the action potential deep into the cell interior, allowing efficient triggering of Ca release and initiation of contraction. Once thought to serve as rather static enablers of excitation-contraction coupling, recent work has provided a newfound appreciation of the plasticity of the t-tubule network's structure and function. Read More

Annu Rev Physiol 2022 02 15;84:533-558. Epub 2021 Nov 15.

Department of Medicine and Pathology and Urology, Columbia University, New York, NY, USA; email:

Urinary tract infection (UTI) is the most common type of urogenital disease. UTI affects the urethra, bladder, ureter, and kidney. A total of 13. Read More

Annu Rev Physiol 2022 02 15;84:59-85. Epub 2021 Nov 15.

Department of Cellular and Molecular Pharmacology, School of Medicine, Mission Bay, University of California, San Francisco, California, USA; email:

The role of central estrogen in cognitive, metabolic, and reproductive health has long fascinated the lay public and scientists alike. In the last two decades, insight into estrogen signaling in the brain and its impact on female physiology is beginning to catch up with the vast information already established for its actions on peripheral tissues. Using newer methods to manipulate estrogen signaling in hormone-sensitive brain regions, neuroscientists are now identifying the molecular pathways and neuronal subtypes required for controlling sex-dependent energy allocation. Read More

Annu Rev Physiol 2022 02 10;84:381-407. Epub 2021 Nov 10.

Department of Physiology, University of California, San Francisco, California, USA; email:

Mitochondria of all tissues convert various metabolic substrates into two forms of energy: ATP and heat. Historically, the primary focus of research in mitochondrial bioenergetics was on the mechanisms of ATP production, while mitochondrial thermogenesis received significantly less attention. Nevertheless, mitochondrial heat production is crucial for the maintenance of body temperature, regulation of the pace of metabolism, and prevention of oxidative damage to mitochondria and the cell. Read More

Annu Rev Physiol 2022 02 9;84:285-306. Epub 2021 Nov 9.

Division of Cardiology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; email:

Each heartbeat is initiated by the action potential, an electrical signal that depolarizes the plasma membrane and activates a cycle of calcium influx via voltage-gated calcium channels, calcium release via ryanodine receptors, and calcium reuptake and efflux via calcium-ATPase pumps and sodium-calcium exchangers. Agonists of the sympathetic nervous system bind to adrenergic receptors in cardiomyocytes, which, via cascading signal transduction pathways and protein kinase A (PKA), increase the heart rate (chronotropy), the strength of myocardial contraction (inotropy), and the rate of myocardial relaxation (lusitropy). These effects correlate with increased intracellular concentration of calcium, which is required for the augmentation of cardiomyocyte contraction. Read More

Annu Rev Physiol 2022 02 9;84:135-155. Epub 2021 Nov 9.

INSERM, Nutrition and Obesities: Systemic Approach (NutriOmics) Research Unit, UMRS U1269, Sorbonne Université, Paris, France; email:

Obesity is a chronic and progressive process affecting whole-body energy balance and is associated with comorbidity development. In addition to increased fat mass, obesity induces white adipose tissue (WAT) inflammation and fibrosis, leading to local and systemic metabolic dysfunctions, such as insulin resistance (IR). Accordingly, limiting inflammation or fibrosis deposition may improve IR and glucose homeostasis. Read More

Annu Rev Physiol 2022 02 9;84:41-58. Epub 2021 Nov 9.

Department of Biological Sciences, Section of Neurobiology, University of Southern California, Los Angeles, California, USA; email:

Sour taste, the taste of acids, is one of the most enigmatic of the five basic taste qualities; its function is unclear and its receptor was until recently unknown. Sour tastes are transduced in taste buds on the tongue and palate epithelium by a subset of taste receptor cells, known as type III cells. Type III cells express a number of unique markers, which allow for their identification and manipulation. Read More

Annu Rev Physiol 2022 02 1;84:611-629. Epub 2021 Nov 1.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; email:

The use of electronic (e)-cigarettes was initially considered a beneficial solution to conventional cigarette smoking cessation. However, paradoxically, e-cigarette use is rapidly growing among nonsmokers, including youth and young adults. In 2019, this rapid growth resulted in an epidemic of hospitalizations and deaths of e-cigarette users (vapers) due to acute lung injury; this novel disease was termed e-cigarette or vaping use-associated lung injury (EVALI). Read More

Annu Rev Physiol 2022 02 1;84:631-654. Epub 2021 Nov 1.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; email:

Chronic obstructive pulmonary disease (COPD) is a complex, heterogeneous, smoking-related disease of significant global impact. The complex biology of COPD is ultimately driven by a few interrelated processes, including proteolytic tissue remodeling, innate immune inflammation, derangements of the host-pathogen response, aberrant cellular phenotype switching, and cellular senescence, among others. Each of these processes are engendered and perpetuated by cells modulating their environment or each other. Read More

Annu Rev Physiol 2022 02 27;84:461-483. Epub 2021 Oct 27.

Division of Gastroenterology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.

Complex multicellular organisms have evolved specific mechanisms to replenish cells in homeostasis and during repair. Here, we discuss how emerging technologies (e.g. Read More

Annu Rev Physiol 2022 02 27;84:157-181. Epub 2021 Oct 27.

Center of Experimental and Molecular Medicine, Division of Infectious Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; email:

Sepsis is expected to have a substantial impact on public health and cost as its prevalence increases. Factors contributing to increased prevalence include a progressively aging population, advances in the use of immunomodulatory agents to treat a rising number of diseases, and immune-suppressing therapies in organ transplant recipients and cancer patients. It is now recognized that sepsis is associated with profound and sustained immunosuppression, which has been implicated as a predisposing factor in the increased susceptibility of patients to secondary infections and mortality. Read More

Annu Rev Physiol 2022 02 27;84:17-40. Epub 2021 Oct 27.

Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, US Department of Health and Human Services, Bethesda, Maryland, USA; email:

β-Arrestin-1 and -2 (also known as arrestin-2 and -3, respectively) are ubiquitously expressed cytoplasmic proteins that dampen signaling through G protein-coupled receptors. However, β-arrestins can also act as signaling molecules in their own right. To investigate the potential metabolic roles of the two β-arrestins in modulating glucose and energy homeostasis, recent studies analyzed mutant mice that lacked or overexpressed β-arrestin-1 and/or -2 in distinct, metabolically important cell types. Read More

Annu Rev Physiol 2022 02 26;84:559-583. Epub 2021 Oct 26.

Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.

Nephrolithiasis is a worldwide problem with increasing prevalence, enormous costs, and significant morbidity. Calcium-containing kidney stones are by far the most common kidney stones encountered in clinical practice, and thus, hypercalciuria is the greatest risk factor for kidney stone formation. Hypercalciuria can result from enhanced intestinal absorption, increased bone resorption, or altered renal tubular transport. Read More

Annu Rev Physiol 2022 02 26;84:409-434. Epub 2021 Oct 26.

Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom.

Cerebral small vessel disease (SVD) is highly prevalent and a common cause of ischemic and hemorrhagic stroke and dementia, yet the pathophysiology is poorly understood. Its clinical expression is highly varied, and prognostic implications are frequently overlooked in clinics; thus, treatment is currently confined to vascular risk factor management. Traditionally, SVD is considered the small vessel equivalent of large artery stroke (occlusion, rupture), but data emerging from human neuroimaging and genetic studies refute this, instead showing microvessel endothelial dysfunction impacting on cell-cell interactions and leading to brain damage. Read More

Annu Rev Physiol 2022 02 21;84:331-354. Epub 2021 Oct 21.

Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington, USA; email:

The vast majority of the brain's vascular length is composed of capillaries, where our understanding of blood flow control remains incomplete. This review synthesizes current knowledge on the control of blood flow across microvascular zones by addressing issues with nomenclature and drawing on new developments from in vivo optical imaging and single-cell transcriptomics. Recent studies have highlighted important distinctions in mural cell morphology, gene expression, and contractile dynamics, which can explain observed differences in response to vasoactive mediators between arteriole, transitional, and capillary zones. Read More

Annu Rev Physiol 2022 02 21;84:485-506. Epub 2021 Oct 21.

Program in Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada; email:

The body depends on its physical barriers and innate and adaptive immune responses to defend against the constant assault of potentially harmful microbes. In turn, successful pathogens have evolved unique mechanisms to adapt to the host environment and manipulate host defenses. (), a human gastric pathogen that is acquired in childhood and persists throughout life, is an example of a bacterium that is very successful at remodeling the host-pathogen interface to promote a long-term persistent infection. Read More

Annu Rev Physiol 2022 02 12;84:113-133. Epub 2021 Oct 12.

Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan; email:

Contrary to earlier beliefs, every cell in the individual is genetically different due to somatic mutations. Consequently, tissues become a mixture of cells with distinct genomes, a phenomenon termed somatic mosaicism. Recent advances in genome sequencing technology have unveiled possible causes of mutations and how they shape the unique mutational landscape of the tissues. Read More

Annu Rev Physiol 2022 02 12;84:355-379. Epub 2021 Oct 12.

Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA; email:

Store-operated Ca entry (SOCE) is a ubiquitous Ca signaling pathway that is evolutionarily conserved across eukaryotes. SOCE is triggered physiologically when the endoplasmic reticulum (ER) Ca stores are emptied through activation of inositol 1,4,5-trisphosphate receptors. SOCE is mediated by the Ca release-activated Ca (CRAC) channels, which are highly Ca selective. Read More

Annu Rev Physiol 2022 02 12;84:307-329. Epub 2021 Oct 12.

EMBL Australia Node in Single Molecule Science, School of Medical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia; email:

Many aspects of mammalian physiology are mechanically regulated. One set of molecules that can mediate mechanotransduction are the mechanically activated ion channels. These ionotropic force sensors are directly activated by mechanical inputs, resulting in ionic flux across the plasma membrane. Read More

Annu Rev Physiol 2022 02 6;84:257-283. Epub 2021 Oct 6.

Department of Physiology, Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; email:

Microtubules are essential cytoskeletal elements found in all eukaryotic cells. The structure and composition of microtubules regulate their function, and the dynamic remodeling of the network by posttranslational modifications and microtubule-associated proteins generates diverse populations of microtubules adapted for various contexts. In the cardiomyocyte, the microtubules must accommodate the unique challenges faced by a highly contractile, rigidly structured, and long-lasting cell. Read More

Annu Rev Physiol 2022 02 6;84:183-207. Epub 2021 Oct 6.

Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6030, USA; email:

Inflammation-adapted hematopoietic stem and progenitor cells (HSPCs) have long been appreciated as key drivers of emergency myelopoiesis, thereby enabling the bone marrow to meet the elevated demand for myeloid cell generation under various stress conditions, such as systemic infection, inflammation, or myelosuppressive insults. In recent years, HSPC adaptations were associated with potential involvement in the induction of long-lived trained immunity and the emergence of clonal hematopoiesis of indeterminate potential (CHIP). Whereas trained immunity has context-dependent effects, protective in infections and tumors but potentially detrimental in chronic inflammatory diseases, CHIP increases the risk for hematological neoplastic disorders and cardiometabolic pathologies. Read More

Annu Rev Physiol 2022 02 6;84:435-459. Epub 2021 Oct 6.

Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA; email:

Mitochondria serve numerous critical cellular functions, rapidly responding to extracellular stimuli and cellular demands while dynamically communicating with other organelles. Mitochondrial function in the gastrointestinal epithelium plays a critical role in maintaining intestinal health. Emerging studies implicate the involvement of mitochondrial dysfunction in inflammatory bowel disease (IBD). Read More

Annu Rev Physiol 2021 02;83:257-278

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA; email:

Adipose tissue depots in distinct anatomical locations mediate key aspects of metabolism, including energy storage, nutrient release, and thermogenesis. Although adipocytes make up more than 90% of adipose tissue volume, they represent less than 50% of its cellular content. Here, I review recent advances in genetic lineage tracing and transcriptomics that reveal the identities of the heterogeneous cell populations constituting mouse and human adipose tissues. Read More

Annu Rev Physiol 2021 02;83:551-576

Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; email:

Pulmonary arterial hypertension (PAH) is characterized by impaired regulation of pulmonary hemodynamics and vascular growth. Alterations of metabolism and bioenergetics are increasingly recognized as universal hallmarks of PAH, as metabolic abnormalities are identified in lungs and hearts of patients, animal models of the disease, and cells derived from lungs of patients. Mitochondria are the primary organelle critically mediating the complex and integrative metabolic pathways in bioenergetics, biosynthetic pathways, and cell signaling. Read More

Annu Rev Physiol 2021 02;83:477-501

Molecular Genetics of Renal Disorders, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy; email:

Uromodulin, a protein exclusively produced by the kidney, is the most abundant urinary protein in physiological conditions. Already described several decades ago, uromodulin has gained the spotlight in recent years, since the discovery that mutations in its encoding gene cause a renal Mendelian disease (autosomal dominant tubulointerstitial kidney disease) and that common polymorphisms are associated with multifactorial disorders, such as chronic kidney disease, hypertension, and cardiovascular diseases. Moreover, variations in uromodulin levels in urine and/or blood reflect kidney functioning mass and are of prognostic value for renal function, cardiovascular events, and overall mortality. Read More