bims-adipim 2023-05-21 papers

bims-adipim

Biomed News

on Adipose immunity and immunometabolism

Issue of 2023–05–21
eleven papers selected by
Matthew C. Sinton, University of Glasgow

Abnormal lipid metabolism in cancer-associated cachexia and potential therapy strategy.
Endothelial cell-derived stem cell factor promotes lipid accumulation through c-Kit-mediated increase of lipogenic enzymes in brown adipocytes.
The impact of cellular senescence in human adipose tissue.
FGF21 has a sex-specific role in calorie-restriction-induced beiging of white adipose tissue in mice.
Differential remodeling of subcutaneous white and interscapular brown adipose tissue by long-term exercise training in aged obese female mice.
PD-L1 stimulation can promote proliferation and survival of leukemic cells by influencing glucose and fatty acid metabolism in acute myeloid leukemia.
The Physiological Regulation of Body Fat Mass.
Navigating the immunometabolic heterogeneity of B cells in murine hepatocellular carcinoma at single cell resolution.
TH17 cell immune adaptation.
Dihydrotestosterone, and Not Testosterone, Enhances the LPS-Induced Inflammatory Cytokine Gene Expression in Human Adipocytes.
Sympathetic tone dictates the impact of lipolysis on FABP4 secretion.

Front Oncol. 2023 ;13 1123567

Abnormal lipid metabolism in cancer-associated cachexia and potential therapy strategy.

Ruoxin Fang, Ling Yan, Zhengkai Liao.

  Cancer-associated cachexia (CAC) is a major characteristic of advanced cancer, associates with almost all types of cancer. Recent studies have found that lipopenia is an important feature of CAC, and it even occurs earlier than sarcopenia. Different types of adipose tissue are all important in the process of CAC. In CAC patients, the catabolism of white adipose tissue (WAT) is increased, leading to an increase in circulating free fatty acids (FFAs), resulting in " lipotoxic". At the same time, WAT also is induced by a variety of mechanisms, browning into brown adipose tissue (BAT). BAT is activated in CAC and greatly increases energy expenditure in patients. In addition, the production of lipid is reduced in CAC, and the cross-talk between adipose tissue and other systems, such as muscle tissue and immune system, also aggravates the progression of CAC. The treatment of CAC is still a vital clinical problem, and the abnormal lipid metabolism in CAC provides a new way for the treatment of CAC. In this article, we will review the mechanism of metabolic abnormalities of adipose tissue in CAC and its role in treatment.

Keywords:  adipose tissue; cachexia; cancer; lipid metabolism; therapy strategy

DOI:  https://doi.org/10.3389/fonc.2023.1123567
Nat Commun. 2023 May 13. 14(1): 2754

Endothelial cell-derived stem cell factor promotes lipid accumulation through c-Kit-mediated increase of lipogenic enzymes in brown adipocytes.

Hyuek Jong Lee, Jueun Lee, Myung Jin Yang, Young-Chan Kim, Seon Pyo Hong, Jung Mo Kim, Geum-Sook Hwang, Gou Young Koh.

Active thermogenesis in the brown adipose tissue (BAT) facilitating the utilization of lipids and glucose is critical for maintaining body temperature and reducing metabolic diseases, whereas inactive BAT accumulates lipids in brown adipocytes (BAs), leading to BAT whitening. Although cellular crosstalk between endothelial cells (ECs) and adipocytes is essential for the transport and utilization of fatty acid in BAs, the angiocrine roles of ECs mediating this crosstalk remain poorly understood. Using single-nucleus RNA sequencing and knock-out male mice, we demonstrate that stem cell factor (SCF) derived from ECs upregulates gene expressions and protein levels of the enzymes for de novo lipogenesis, and promotes lipid accumulation by activating c-Kit in BAs. In the early phase of lipid accumulation induced by denervation or thermoneutrality, transiently expressed c-Kit on BAs increases the protein levels of the lipogenic enzymes via PI3K and AKT signaling. EC-specific SCF deletion and BA-specific c-Kit deletion attenuate the induction of the lipogenic enzymes and suppress the enlargement of lipid droplets in BAs after denervation or thermoneutrality in male mice. These data provide insight into SCF/c-Kit signaling as a regulator that promotes lipid accumulation through the increase of lipogenic enzymes in BAT when thermogenesis is inhibited.

DOI: https://doi.org/10.1038/s41467-023-38433-5
J Cell Commun Signal. 2023 May 17.

The impact of cellular senescence in human adipose tissue.

Annika Nerstedt, Ulf Smith.

  In the last decades the prevalence of obesity has increased dramatically, and the worldwide epidemic of obesity and related metabolic diseases has contributed to an increased interest for the adipose tissue (AT), the primary site for storage of lipids, as a metabolically dynamic and endocrine organ. Subcutaneous AT is the depot with the largest capacity to store excess energy and when its limit for storage is reached hypertrophic obesity, local inflammation, insulin resistance and ultimately type 2 diabetes (T2D) will develop. Hypertrophic AT is also associated with a dysfunctional adipogenesis, depending on the inability to recruit and differentiate new mature adipose cells. Lately, cellular senescence (CS), an aging mechanism defined as an irreversible growth arrest that occurs in response to various cellular stressors, such as telomere shortening, DNA damage and oxidative stress, has gained a lot of attention as a regulator of metabolic tissues and aging-associated conditions. The abundance of senescent cells increases not only with aging but also in hypertrophic obesity independent of age. Senescent AT is characterized by dysfunctional cells, increased inflammation, decreased insulin sensitivity and lipid storage. AT resident cells, such as progenitor cells (APC), non-proliferating mature cells and microvascular endothelial cells are affected with an increased senescence burden. Dysfunctional APC have both an impaired adipogenic and proliferative capacity. Interestingly, human mature adipose cells from obese hyperinsulinemic individuals have been shown to re-enter the cell cycle and senesce, which indicates an increased endoreplication. CS was also found to be more pronounced in mature cells from T2D individuals, compared to matched non-diabetic individuals, with decreased insulin sensitivity and adipogenic capacity. Factors associated with cellular senescence in human adipose tissue.

Keywords:  Adipose tissue; Cellular senescence; Inflammation; Insulin resistance; Obesity; Type 2 diabetes

DOI:  https://doi.org/10.1007/s12079-023-00769-4
Aging Biol. 2022 ;pii: 3. [Epub ahead of print]1

FGF21 has a sex-specific role in calorie-restriction-induced beiging of white adipose tissue in mice.

Mariah F Calubag, Ismail Ademi, Chung-Yang Yeh, Reji Babygirija, Heidi H Pak, Alyssa M Bhoopat, Ildiko Kasza, Cara L Green, Michelle M Sonsalla, Dudley W Lamming.

Calorie restriction (CR) promotes healthspan and extends the lifespan of diverse organisms, including mice, and there is intense interest in understanding the molecular mechanisms by which CR functions. Some studies have demonstrated that CR induces fibroblast growth factor 21 (FGF21), a hormone that regulates energy balance and that when overexpressed, promotes metabolic health and longevity in mice, but the role of FGF21 in the response to CR has not been fully investigated. We directly examined the role of FGF21 in the physiological and metabolic response to a CR diet by feeding Fgf21-/- and wild-type control mice either ad libitum (AL) diet or a 30% CR diet for 15 weeks. Here, we find that FGF21 is largely dispensable for CR-induced improvements in body composition and energy balance, but that lack of Fgf21 blunts CR-induced changes aspects of glucose regulation and insulin sensitivity in females. Surprisingly, despite not affecting CR-induced changes in energy expenditure, loss of Fgf21 significantly blunts CR-induced beiging of white adipose tissue in male but not female mice. Our results shed new light on the molecular mechanisms involved in the beneficial effects of a CR diet, clarify that FGF21 is largely dispensable for the metabolic effects of a CR diet, and highlight a sex-dependent role for FGF21 in the molecular adaptation of white adipose tissue to CR.

Keywords: FGF21; beiging; calorie restriction; glucose homeostasis; metabolic health; white adipose tissue
J Physiol Biochem. 2023 May 19.

Differential remodeling of subcutaneous white and interscapular brown adipose tissue by long-term exercise training in aged obese female mice.

Elisa Félix-Soriano, Neira Sáinz, Eva Gil-Iturbe, Rosa Castilla-Madrigal, Jon Celay, Marta Fernández-Galilea, Álvaro Pejenaute, M Pilar Lostao, José A Martínez-Climent, María J Moreno-Aliaga.

  Obesity exacerbates aging-induced adipose tissue dysfunction. This study aimed to investigate the effects of long-term exercise on inguinal white adipose tissue (iWAT) and interscapular brown adipose tissue (iBAT) of aged obese mice. Two-month-old female mice received a high-fat diet for 4 months. Then, six-month-old diet-induced obese animals were allocated to sedentarism (DIO) or to a long-term treadmill training (DIOEX) up to 18 months of age. In exercised mice, iWAT depot revealed more adaptability, with an increase in the expression of fatty acid oxidation genes (Cpt1a, Acox1), and an amelioration of the inflammatory status, with a favorable modulation of pro/antiinflammatory genes and lower macrophage infiltration. Additionally, iWAT of trained animals showed an increment in the expression of mitochondrial biogenesis (Pgc1a, Tfam, Nrf1), thermogenesis (Ucp1), and beige adipocytes genes (Cd137, Tbx1). In contrast, iBAT of aged obese mice was less responsive to exercise. Indeed, although an increase in functional brown adipocytes genes and proteins (Pgc1a, Prdm16 and UCP1) was observed, few changes were found on inflammation-related and fatty acid metabolism genes. The remodeling of iWAT and iBAT depots occurred along with an improvement in the HOMA index for insulin resistance and in glucose tolerance. In conclusion, long-term exercise effectively prevented the loss of iWAT and iBAT thermogenic properties during aging and obesity. In iWAT, the long-term exercise program also reduced the inflammatory status and stimulated a fat-oxidative gene profile. These exercise-induced adipose tissue adaptations could contribute to the beneficial effects on glucose homeostasis in aged obese mice.

Keywords:  Aging; Brown adipose tissue; Female; Obesity; Treadmill training; White adipose tissue

DOI:  https://doi.org/10.1007/s13105-023-00964-2
BMC Cancer. 2023 May 16. 23(1): 447

PD-L1 stimulation can promote proliferation and survival of leukemic cells by influencing glucose and fatty acid metabolism in acute myeloid leukemia.

Mojdeh Soltani, Mustafa Ghanadian, Behrooz Ghezelbash, Abolfazl Shokouhi, Andrey A Zamyatnin, Alexandr V Bazhin, Mazdak Ganjalikhani-Hakemi.

   BACKGROUND: Leukemic cell metabolism plays significant roles in their proliferation and survival. These metabolic adaptations are under regulation by different factors. Programmed Death Ligand -1 (CD-274) is one of the immune checkpoint ligands that do not only cause the immune escape of cancer cells, but also have some intracellular effects in these cells. PD-L1 is overexpressed on leukemic stem cells and relates with poor prognosis of AML. In this study, we investigated effects of PD-L1 stimulation on critical metabolic pathways of glucose and fatty acid metabolisms that have important roles in proliferation and survival of leukemic cells.
METHODS: After confirmation of PD-L1 expression by flow cytometry assay, we used recombinant protein PD-1 for stimulation of the PD-L1 on two AML cell lines, HL-60 and THP-1. Then we examined the effect of PD-L1 stimulation on glucose and fatty acid metabolism in cells at the genomic and metabolomic levels in a time dependent manner. We investigated expression changes of rate limiting enzymes of theses metabolic pathways (G6PD, HK-2, CPT1A, ATGL1 and ACC1) by qRT-PCR and also the relative abundance changes of free fatty acids of medium by GC.
RESULTS: We identified a correlation between PD-L1 stimulation and both fatty acid and glucose metabolism. The PD-L1 stimulated cells showed an influence in the pentose phosphate pathway and glycolysis by increasing expression of G6PD and HK-2 (P value = 0.0001). Furthermore, PD-L1 promoted fatty acid β-oxidation by increasing expression of CPT1A (P value = 0.0001), however, their fatty acid synthesis was decreased by reduction of ACC1 expression (P value = 0.0001).
CONCLUSION: We found that PD-L1 can promote proliferation and survival of AML stem cells probably through some metabolic changes in leukemic cells. Pentose phosphate pathway that has a critical role in cell proliferation and fatty acids β-oxidation that promote cell survival, both are increased by PD-L1 stimulation on AML cells.

Keywords:  AML; Acute myeloid leukemia; Fatty acid oxidation; Immunometabolism; PD-1; Pentose phosphate pathway; Programmed death ligand-1

DOI:  https://doi.org/10.1186/s12885-023-10947-7
Gastroenterol Clin North Am. 2023 Jun;pii: S0889-8553(23)00029-8. [Epub ahead of print]52(2): 295-310

The Physiological Regulation of Body Fat Mass.

Priya Sumithran.

  Disturbances inbody weight and adiposity in both humans and animals are met by compensatory adjustments in energy intake and energy expenditure, suggesting that body weight or fat is regulated. From a clinical viewpoint, this is likely to contribute to the difficulty that many people with obesity have in maintaining weight loss. Finding ways to modify these physiologic responses is likely to improve the long-term success of obesity treatments.

Keywords:  Body fat; Body weight; Obesity; Weight regulation

DOI:  https://doi.org/10.1016/j.gtc.2023.03.003
Int Immunopharmacol. 2023 May 12. pii: S1567-5769(23)00578-7. [Epub ahead of print]120 110257

Navigating the immunometabolic heterogeneity of B cells in murine hepatocellular carcinoma at single cell resolution.

Xindong Zhao, Huanran Zhang, Yiru Han, Chengyu Fang, Jingqi Liu.

  Induction of antitumor immunity is critical for the therapeutic efficacy of hepatocellular carcinoma (HCC) immunotherapy. The cellular metabolic state underpins the effector function of immune cells, yet our understanding of the phenotypic and metabolic heterogeneity of B cells within HCC microenvironment is poorly developed. Herein, we investigated the composition, distribution, phenotype, function and metabolic profiles of B-cell subsets in HCC and adjacent liver tissues from an orthotopic HCC mouse model using single-cell RNA sequencing (scRNA-seq). Our results identified six B-cell clusters, which can be classified into plasma cells and activated and exhausted B cells according to marker expression, functional and temporal distribution. Exhausted B cells exhibited low metabolic activities and impaired effector functions. Activated B and plasma cells showed higher metabolic activity than exhausted B cells, but there were clear differences in their metabolic profiles. In addition, we found that the effector function of exhausted B cells was further diminished in HCC tissues compared with adjacent liver tissues, but their metabolic activity was significantly enhanced. Collectively, we comprehensively characterized the metabolic profile and alterations in B-cell subsets in HCC, which contributes to the understanding of B-cell immunology in HCC and lays the foundation for exploring novel targets in HCC immunotherapy.

Keywords:  B cells; Hepatocellular carcinoma; Immunometabolism; single-cell RNA-sequencing

DOI:  https://doi.org/10.1016/j.intimp.2023.110257
Curr Opin Immunol. 2023 May 10. pii: S0952-7915(23)00052-3. [Epub ahead of print]83 102333

TH17 cell immune adaptation.

Theodora Agalioti, Filippo Cortesi, Nicola Gagliani.

At mucosal barriers, the T helper 17 (TH17) cell population plays a fundamental role in controlling tissue homeostasis. The adaptability of this population to a more pro-inflammatory or anti-inflammatory function - that is, their functional plasticity and consequently heterogeneity - primarily depends on the environment. We would like to term this process environmental immune adaptation. Interfering with TH17 cell adaptation leads to pathological consequences, including development of immune-mediated inflammatory diseases or even cancer. Several molecular mechanisms have been shown to participate in this process and recently, a better understanding of the transcriptional and metabolic profiling of TH17 cells has shed light on a new level of complexity. Here, we offer a summary on the role of TH17 cell plasticity in inflammatory diseases and cancer as well as the latest discoveries and controversies regarding the mechanisms that control the adaptability of the TH17 cell population.

DOI: https://doi.org/10.1016/j.coi.2023.102333
Biomedicines. 2023 Apr 17. pii: 1194. [Epub ahead of print]11(4):

Dihydrotestosterone, and Not Testosterone, Enhances the LPS-Induced Inflammatory Cytokine Gene Expression in Human Adipocytes.

Angelo Di Vincenzo, Marnie Granzotto, Marika Crescenzi, Vincenzo Vindigni, Roberto Vettor, Marco Rossato.

   BACKGROUND: The development of obesity-related complications lies in the low-grade inflammatory state consequent to adipocyte dysfunction. The direct involvement of sex hormones in adipose tissue inflammation has been previously suggested, but the evidence is scarce. In this study, we evaluated the effects of sex steroids on the in-vitroexpression of inflammatory mediators in human-derived adipocytes before and after lipopolysaccharide (LPS) exposure.
METHODS: Human adipocytes were differentiated from the vascular stromal fraction of adipose tissue samples of subjects undergoing abdominoplasty. We evaluated MCP-1, IL-1β, IL-6, and TNF-α gene expression in the presence of the main sex steroids, testosterone (T), and 17β-estradiol (E). Furthermore, we analyzed the effects of adipocytes exposure to the non-aromatizable androgen dihydrotestosterone (DHT), together with the effects of adipocytes pre-incubation with the aromatase inhibitor anastrozole alone (A), and in combination with T (A/T) before incubation with LPS.
RESULTS: DHT, but not T, significantly enhanced the LPSinduction of MCP-1, IL-1β, IL-6, and TNF-α. Intriguingly, the exposure of adipocytes with A/T dramatically increased the LPS-induced expression of all considered inflammatory cytokines, even more than a hundred-fold.
CONCLUSIONS: DHT and A/T dramatically enhance LPS-induced inflammatory cytokine expression in human-derived adipocytes. These results confirm the involvement of sex hormones in adipose tissue inflammation, suggesting a specific role for non-aromatizable androgens as the amplificatory sex hormones of the inflammatory response.

Keywords:  adipocytokines; adipose tissue; inflammation; testosterone

DOI:  https://doi.org/10.3390/biomedicines11041194
J Lipid Res. 2023 May 10. pii: S0022-2275(23)00059-7. [Epub ahead of print] 100386

Sympathetic tone dictates the impact of lipolysis on FABP4 secretion.

Kacey J Prentice, Alexandra Lee, Paulina Cedillo, Karen E Inouye, Meric Erikci Ertunc, Jillian K Riveros, Grace Yankun Lee, Gökhan S Hotamisligil.

  Levels of circulating FABP4 protein are strongly associated with obesity and metabolic disease in both mice and humans, and secretion is stimulated by ß-adrenergic stimulation both in vivo and in vitro. Previously, lipolysis-induced FABP4 secretion was found to be significantly reduced upon pharmacological inhibition of adipose triglyceride lipase (ATGL), and was absent from adipose tissue explants from mice specifically lacking ATGL in their adipocytes (ATGLAdpKO). Here we find that upon activation of ß-adrenergic receptors in vivo, ATGLAdpKO mice unexpectedly exhibited significantly higher levels of circulating FABP4 as compared to ATGLfl/fl controls, despite no corresponding induction of lipolysis. We generated an additional model with adipocyte-specific deletion of both FABP4 and ATGL (ATGL/FABP4AdpKO) to evaluate the cellular source of this circulating FABP4. In these animals, there was no evidence of lipolysis-induced FABP4 secretion, indicating that the source of elevated FABP4 levels in ATGLAdpKO mice was indeed from the adipocytes. ATGLAdpKO mice exhibited significantly elevated corticosterone levels, which positively correlated with plasma FABP4 levels. Pharmacological inhibition of sympathetic signaling during lipolysis using hexamethonium, or housing mice at thermoneutrality to chronically reduce sympathetic tone significantly reduced FABP4 secretion in ATGLAdpKO mice compared to controls. Therefore, activity of a key enzymatic step of lipolysis mediated by ATGL, per se, is not required for in vivo stimulation of FABP4 secretion from adipocytes, which can be induced through sympathetic signaling.

Keywords:  Adipocytes; Adipose Triglyceride Lipase (ATGL); Adipose tissue; Fatty Acid Binding Proteins; Fatty Acid Transport; Lipolysis; Sympathetic Tone

DOI:  https://doi.org/10.1016/j.jlr.2023.100386