The manner in which white adipose tissue (WAT) expands and remodels directly impacts the risk of developing metabolic syndrome in obesity. Preferential accumulation of visceral WAT is associated with increased risk for insulin resistance, whereas subcutaneous WAT expansion is protective. Moreover, pathologic WAT remodeling, typically characterized by adipocyte hypertrophy, chronic inflammation, and fibrosis, is associated with insulin resistance. Healthy WAT expansion, observed in the “metabolically healthy” obese, is generally associated with the presence of smaller and more numerous adipocytes, along with lower degrees of inflammation and fibrosis. Here, we highlight recent human and rodent studies that support the notion that the ability to recruit new fat cells through adipogenesis is a critical determinant of healthy adipose tissue distribution and remodeling in obesity. Furthermore, we discuss recent advances in our understanding of the identity of tissue-resident progenitor populations in WAT made possible through single-cell RNA sequencing analysis. A better understanding of adipose stem cell biology and adipogenesis may lead to novel strategies to uncouple obesity from metabolic disease.
Lavanya Vishvanath, Rana K. Gupta
The metabolic syndrome (MetS) is a constellation of risk factors that, if left untreated, will often progress to greater metabolic defects such as type 2 diabetes and nonalcoholic fatty liver disease. While these risk factors have been established for over 40 years, the definition of MetS warrants reconsideration in light of the substantial data that have emerged from studies of the gut microbiome. In this Review we present the existing recent literature that supports the gut microbiome’s potential influence on the various risk factors of MetS. The interplay of the intestinal microbiota with host metabolism has been shown to be mediated by a myriad of factors, including a defective gut barrier, bile acid metabolism, antibiotic use, and the pleiotropic effects of microbially produced metabolites. These data show that events that start in the gut, often in response to external cues such as diet and circadian disruption, have far-reaching effects beyond the gut.
Kruttika Dabke, Gustaf Hendrick, Suzanne Devkota
Although obesity is typically associated with metabolic dysfunction and cardiometabolic diseases, some people with obesity are protected from many of the adverse metabolic effects of excess body fat and are considered “metabolically healthy.” However, there is no universally accepted definition of metabolically healthy obesity (MHO). Most studies define MHO as having either 0, 1, or 2 metabolic syndrome components, whereas many others define MHO using the homeostasis model assessment of insulin resistance (HOMA-IR). Therefore, numerous people reported as having MHO are not metabolically healthy, but simply have fewer metabolic abnormalities than those with metabolically unhealthy obesity (MUO). Nonetheless, a small subset of people with obesity have a normal HOMA-IR and no metabolic syndrome components. The mechanism(s) responsible for the divergent effects of obesity on metabolic health is not clear, but studies conducted in rodent models suggest that differences in adipose tissue biology in response to weight gain can cause or prevent systemic metabolic dysfunction. In this article, we review the definition, stability over time, and clinical outcomes of MHO, and discuss the potential factors that could explain differences in metabolic health in people with MHO and MUO — specifically, modifiable lifestyle factors and adipose tissue biology. Better understanding of the factors that distinguish people with MHO and MUO can produce new insights into mechanism(s) responsible for obesity-related metabolic dysfunction and disease.
Gordon I. Smith, Bettina Mittendorfer, Samuel Klein
Obesity originates from an imbalance between caloric intake and energy expenditure that promotes adipose tissue expansion, which is necessary to buffer nutrient excess. Patients with higher visceral fat mass are at a higher risk of developing severe complications such as type 2 diabetes and cardiovascular and liver diseases. However, increased fat mass does not fully explain obesity’s propensity to promote metabolic diseases. With chronic obesity, adipose tissue undergoes major remodeling, which can ultimately result in unresolved chronic inflammation leading to fibrosis accumulation. These features drive local tissue damage and initiate and/or maintain multiorgan dysfunction. Here, we review the current understanding of adipose tissue remodeling with a focus on obesity-induced adipose tissue fibrosis and its relevance to clinical manifestations.
Geneviève Marcelin, Ana Letícia M. Silveira, Laís Bhering Martins, Adaliene V.M. Ferreira, Karine Clément
Adipose tissue plays important roles in regulating whole-body energy metabolism through its storage function in white adipocytes and its dissipating function in brown and beige adipocytes. Adipose tissue also produces a variety of secreted factors called adipocytokines, including leptin and adiponectin. Furthermore, recent studies have suggested the important roles of extracellular vesicles of endosomal origin termed exosomes, which are secreted from adipocytes and other cells in adipose tissue and influence whole-body glucose and lipid metabolism. Adiponectin is known to be a pleiotropic organ-protective protein that is exclusively produced by adipocytes and decreased in obesity. Adiponectin accumulates in tissues such as heart, muscle, and vascular endothelium through binding with T-cadherin, a glycosylphosphatidylinositol-anchored (GPI-anchored) cadherin. Recently, adiponectin was found to enhance exosome biogenesis and secretion, leading to a decrease in cellular ceramides, excess of which is known to cause insulin resistance and cardiovascular disease phenotypes. These findings support the hypothesis that adipose tissue metabolism systemically regulates exosome production and whole-body metabolism through exosomes. This review focuses on intra-adipose and interorgan communication by exosomes, adiponectin-stimulated exosome production, and their dysregulation in metabolic diseases.
Shunbun Kita, Norikazu Maeda, Iichiro Shimomura
Vaccine development against tuberculosis (TB) is based on the induction of adaptive immune responses endowed with long-term memory against mycobacterial antigens. Memory B and T cells initiate a rapid and robust immune response upon encounter with Mycobacterium tuberculosis, thus achieving long-lasting protection against infection. Recent studies have shown, however, that innate immune cell populations such as myeloid cells and NK cells also undergo functional adaptation after infection or vaccination, a de facto innate immune memory that is also termed trained immunity. Experimental and epidemiological data have shown that induction of trained immunity contributes to the beneficial heterologous effects of vaccines such as bacille Calmette-Guérin (BCG), the licensed TB vaccine. Moreover, increasing evidence argues that trained immunity also contributes to the anti-TB effects of BCG vaccination. An interaction among immunological signals, metabolic rewiring, and epigenetic reprogramming underlies the molecular mechanisms mediating trained immunity in myeloid cells and their bone marrow progenitors. Future studies are warranted to explore the untapped potential of trained immunity to develop a future generation of TB vaccines that would combine innate and adaptive immune memory induction.
Shabaana A. Khader, Maziar Divangahi, Willem Hanekom, Philip C. Hill, Markus Maeurer, Karen W. Makar, Katrin D. Mayer-Barber, Musa M. Mhlanga, Elisa Nemes, Larry S. Schlesinger, Reinout van Crevel, Ramakrishna Vankalayapati, Ramnik J. Xavier, Mihai G. Netea, on behalf of the Bill and Melinda Gates Foundation Collaboration for TB Vaccine Discovery Innate Immunity Working Group18
IgG antibodies are secreted from B cells and bind to a variety of pathogens to control infections as well as contribute to inflammatory diseases. Many of the functions of IgGs are mediated through Fcγ receptors (FcγRs), which transduce interactions with immune complexes, leading to a variety of cellular outcomes depending on the FcγRs and cell types engaged. Which FcγRs and cell types will be engaged during an immune response depends on the structure of Fc domains within immune complexes that are formed when IgGs bind to cognate antigen(s). Recent studies have revealed an unexpected degree of structural variability in IgG Fc domains among people, driven primarily by differences in IgG subclasses and N-linked glycosylation of the CH2 domain. This translates, in turn, to functional immune diversification through type I and type II FcγR–mediated cellular functions. For example, Fc domain sialylation triggers conformational changes of IgG1 that enable interactions with type II FcγRs; these receptors mediate cellular functions including antiinflammatory activity or definition of thresholds for B cell selection based on B cell receptor affinity. Similarly, presence or absence of a core fucose alters type I FcγR binding of IgG1 by modulating the Fc’s affinity for FcγRIIIa, thereby altering its proinflammatory activity. How heterogeneity in IgG Fc domains contributes to human immune diversity is now being elucidated, including impacts on vaccine responses and susceptibility to disease and its sequelae during infections. Here, we discuss how Fc structures arising from sialylation and fucosylation impact immunity, focusing on responses to vaccination and infection. We also review work defining individual differences in Fc glycosylation, regulation of Fc glycosylation, and clinical implications of these pathways.
Taia T. Wang, Jeffrey V. Ravetch
Natural killer (NK) cells are innate cytotoxic lymphocytes involved in the surveillance and elimination of cancer. As we have learned more and more about the mechanisms NK cells employ to recognize and eliminate tumor cells, and how, in turn, cancer evades NK cell responses, we have gained a clear appreciation that NK cells can be harnessed in cancer immunotherapy. Here, we review the evidence for NK cells’ critical role in combating transformed and malignant cells, and how cancer immunotherapies potentiate NK cell responses for therapeutic purposes. We highlight cutting-edge immunotherapeutic strategies in preclinical and clinical development such as adoptive NK cell transfer, chimeric antigen receptor–expressing NK cells (CAR-NKs), bispecific and trispecific killer cell engagers (BiKEs and TriKEs), checkpoint blockade, and oncolytic virotherapy. Further, we describe the challenges that NK cells face (e.g., postsurgical dysfunction) that must be overcome by these therapeutic modalities to achieve cancer clearance.
Jonathan J. Hodgins, Sarwat T. Khan, Maria M. Park, Rebecca C. Auer, Michele Ardolino
Patients with type 1 or type 2 diabetes have an insufficiency in their functional β cell mass. To advance diabetes treatment and to work toward a cure, a better understanding of how to protect the pancreatic β cells against autoimmune or metabolic assaults (e.g., obesity, gestation) will be required. Over the past decades, β cell protection has been extensively investigated in rodents both in vivo and in vitro using isolated islets or rodent β cell lines. Transferring these rodent data to humans has long been challenging, at least partly for technical reasons: primary human islet preparations were scarce and functional human β cell lines were lacking. In 2011, we described a robust protocol of targeted oncogenesis in human fetal pancreas and produced the first functional human β cell line, and in subsequent years additional lines with specific traits. These cell lines are currently used by more than 150 academic and industrial laboratories worldwide. In this Review, we first explain how we developed the human β cell lines and why we think we succeeded where others, despite major efforts, did not. Next, we discuss the use of such functional human β cell lines and share some perspectives on their use to advance diabetes research.
Raphael Scharfmann, Willem Staels, Olivier Albagli
In a society where physical activity is limited and food supply is abundant, metabolic diseases are becoming a serious epidemic. Metabolic syndrome (MetS) represents a cluster of metabolically related symptoms such as obesity, hypertension, dyslipidemia, and carbohydrate intolerance, and significantly increases type 2 diabetes mellitus risk. Insulin resistance and hyperinsulinemia are consistent characteristics of MetS, but which of these features is the initiating insult is still widely debated. Regardless, both of these conditions trigger adverse responses from the pancreatic β cell, which is responsible for producing, storing, and releasing insulin to maintain glucose homeostasis. The observation that the degree of β cell dysfunction correlates with the severity of MetS highlights the need to better understand β cell dysfunction in the development of MetS. This Review focuses on the current understanding from rodent and human studies of the progression of β cell responses during the development of MetS, as well as recent findings addressing the complexity of β cell identity and heterogeneity within the islet during disease progression. The differential responses observed in β cells together with the heterogeneity in disease phenotypes within the patient population emphasize the need to better understand the mechanisms behind β cell adaptation, identity, and dysfunction in MetS.
Laura I. Hudish, Jane E.B. Reusch, Lori Sussel
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