Leptin: molecular mechanisms, systemic pro-inflammatory effects, and clinical implications

Leptin, the adipokine produced mainly by the white adipose tissue, plays important roles not only in the regulation of food intake, but also in controlling immunity and inflammation. It has been widely demonstrated that the absence of leptin leads to immune defects in animal and human models, ultimately increasing mortality. Leptin also regulates inflammation by means of actions on its receptor, that is widely spread across different immune cell populations. The molecular mechanisms by which leptin determines its biological actions have also been recently elucidated, and three intracellular pathways have been implicated in leptin actions: JAK-STAT, PI3K, and ERK 1/2. These pathways are closely regulated by intracellular proteins that decrease leptin biological activity. In this review, we discuss the molecular mechanisms by which leptin regulates immunity and inflammation, and associate those mechanisms with chronic inflammatory disorders. Arq Bras Endocrinol Metab. 2012;56(9):597-607

Download Full-text

miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice

Journal of Experimental Medicine ◽

10.1084/jem.20101823 ◽

2011 ◽

Vol 208 (6) ◽

pp. 1189-1201 ◽

Cited By ~ 528

Author(s):

Mark P. Boldin ◽

Konstantin D. Taganov ◽

Dinesh S. Rao ◽

Lili Yang ◽

Jimmy L. Zhao ◽

...

Keyword(s):

Molecular Mechanisms ◽

Immune Cell ◽

Myeloid Cell ◽

Genetically Engineered ◽

Biological Processes ◽

Targeted Deletion ◽

Genetically Engineered Mice ◽

Immune Defects ◽

Molecular Brake

Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ∼22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation.

Download Full-text

Generation of immune cell containing adipose organoids for in vitro analysis of immune metabolism

Scientific Reports ◽

10.1038/s41598-020-78015-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Jacqueline Taylor ◽

Julia Sellin ◽

Lars Kuerschner ◽

Lennart Krähl ◽

Yasmin Majlesain ◽

...

Keyword(s):

Adipose Tissue ◽

Adipocyte Differentiation ◽

Immune Cell ◽

Stromal Vascular Fraction ◽

Cell Populations ◽

Endocrine Organ ◽

Vitro Analysis ◽

In Vitro Analysis ◽

Better Than

AbstractAdipose tissue is an organized endocrine organ with important metabolic and immunological functions and immune cell-adipocyte crosstalk is known to drive various disease pathologies. Suitable 3D adipose tissue organoid models often lack resident immune cell populations and therefore require the addition of immune cells isolated from other organs. We have created the first 3D adipose tissue organoid model which could contain and maintain resident immune cell populations of the stromal vascular fraction (SVF) and proved to be effective in studying adipose tissue biology in a convenient manner. Macrophage and mast cell populations were successfully confirmed within our organoid model and were maintained in culture without the addition of growth factors. We demonstrated the suitability of our model for monitoring the lipidome during adipocyte differentiation in vitro and confirmed that this model reflects the physiological lipidome better than standard 2D cultures. In addition, we applied mass spectrometry-based lipidomics to track lipidomic changes in the lipidome upon dietary and immunomodulatory interventions. We conclude that this model represents a valuable tool for immune-metabolic research.

Download Full-text

Stromal-Immune Cell Crosstalk Maintains Type 2 Immune Cell Populations within Visceral Adipose Tissue

Immunometabolism ◽

10.20900/immunometab20200018 ◽

2020 ◽

Keyword(s):

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Immune Cell ◽

Cell Populations ◽

Visceral Adipose ◽

Cell Crosstalk

Download Full-text

Circulating sex steroids coregulate adipose tissue immune cell populations in healthy men

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00075.2017 ◽

2017 ◽

Vol 313 (5) ◽

pp. E528-E539 ◽

Cited By ~ 2

Author(s):

Katya B. Rubinow ◽

Jing H. Chao ◽

Derek Hagman ◽

Mario Kratz ◽

Brian Van Yserloo ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Adipose Tissue ◽

Immune Cells ◽

Immune Cell ◽

Sex Steroid ◽

Cell Populations ◽

Male Hypogonadism ◽

Healthy Men ◽

Testosterone Gel

Male hypogonadism results in changes in body composition characterized by increases in fat mass. Resident immune cells influence energy metabolism in adipose tissue and could promote increased adiposity through paracrine effects. We hypothesized that manipulation of circulating sex steroid levels in healthy men would alter adipose tissue immune cell populations. Subjects ( n = 44 men, 19–55 yr of age) received 4 wk of treatment with the gonadotropin-releasing hormone receptor antagonist acyline with daily administration of 1) placebo gel, 2) 1.25 g testosterone gel (1.62%), 3) 5 g testosterone gel, or 4) 5 g testosterone gel with an aromatase inhibitor. Subcutaneous adipose tissue biopsies were performed at baseline and end-of-treatment, and adipose tissue immune cells, gene expression, and intra-adipose estrogen levels were quantified. Change in serum total testosterone level correlated inversely with change in the number of CD3+ (β = −0.36, P = 0.04), CD4+ (β = −0.34, P = 0.04), and CD8+ (β = −0.33, P = 0.05) T cells within adipose tissue. Change in serum 17β-estradiol level correlated inversely with change in the number of adipose tissue macrophages (ATMs) (β = −0.34, P = 0.05). A negative association also was found between change in serum testosterone and change in CD11c+ ATMs (β = −0.41, P = 0.01). Overall, sex steroid deprivation was associated with increases in adipose tissue T cells and ATMs. No associations were found between changes in serum sex steroid levels and changes in adipose tissue gene expression. Circulating sex steroid levels may regulate adipose tissue immune cell populations. These exploratory findings highlight a possible novel mechanism that could contribute to increased metabolic risk in hypogonadal men.

Download Full-text

Possible role of transforming growth factor β as a marker cytokine of type 3 T-helpers in atopic dermatitis pathogenesis

Bulletin of Siberian Medicine ◽

10.20538/1682-0363-2004-3-27-31 ◽

2004 ◽

Vol 3 (3) ◽

pp. 27-31

Author(s):

N. A. Pronina ◽

V. S. Sviridova ◽

A. A. Denisov ◽

V. V. Klimov ◽

Ye. N. Kologrivova

Keyword(s):

Atopic Dermatitis ◽

Biological Activity ◽

Growth Factor ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Allergic Inflammation ◽

Transforming Growth Factor Β ◽

Cell Populations ◽

Type 3

The role of transforming growth factor β (TGF-β) in atopic dermatitis pathogenesis is discussed basing on the analysis of existing data of cellular and molecular mechanisms of allergic inflammation. Up-to date data of the main T-helper (T-h) lymphocyte subpopulations including Tx1, Tx2, Tx3 has been presented. Functions of regulatory T-cell populations and produced cytokines have been described. The main attention has been accented on the TGF-β structure and biological activity as a main Tx3 cytokine. The current information of TGF-β influence on different cell populations and its biological activity realization mechanism is thoroughly discussed. Information relating to the mechanism of cytokine regulation during atopic dermatitis has been summarized. A deep analysis of possible participation of TGF-β in disbalance formation on Tx1 and Tx2 levels, in disturbances of histological derma structure and allergic inflammation timing has been made.

Download Full-text

Shifts of Immune Cell Populations Differ in Response to Different Effectors of Beige Remodeling of Adipose Tissue

iScience ◽

10.1016/j.isci.2020.101765 ◽

2020 ◽

Vol 23 (12) ◽

pp. 101765

Author(s):

Nabil Rabhi ◽

Anna C. Belkina ◽

Kathleen Desevin ◽

Briana Noel Cortez ◽

Stephen R. Farmer

Keyword(s):

Adipose Tissue ◽

Immune Cell ◽

Cell Populations

Download Full-text

Faculty Opinions recommendation of An Integrated Understanding of the Molecular Mechanisms How Adipose Tissue Metabolism Affects Long-Term Body Weight Maintenance.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734356607.793555902 ◽

2019 ◽

Author(s):

Marleen van Baak

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Molecular Mechanisms ◽

Weight Maintenance ◽

Adipose Tissue Metabolism ◽

Tissue Metabolism

Download Full-text

The Mechanisms Behind the Biological Activity of Flavonoids

Current Medicinal Chemistry ◽

10.2174/0929867325666180706104829 ◽

2019 ◽

Vol 26 (39) ◽

pp. 6976-6990 ◽

Cited By ~ 12

Author(s):

Ana María González-Paramás ◽

Begoña Ayuda-Durán ◽

Sofía Martínez ◽

Susana González-Manzano ◽

Celestino Santos-Buelga

Keyword(s):

Gene Expression ◽

Biological Activity ◽

Phenolic Compounds ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Radical Scavenging ◽

Model Organism ◽

Stress Theory ◽

Radical Scavenging Properties

: Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

Download Full-text