bims-adipim 2023-07-30 papers

Issue of 2023–07–30
seven papers selected by
Matthew C. Sinton, University of Glasgow

Nat Metab. 2023 Jul;5(7): 1088-1100

Interleukin-17 as a key player in neuroimmunometabolism.

Aaron Douglas, Brenneth Stevens, Lydia Lynch.

In mammals, interleukin (IL)-17 cytokines are produced by innate and adaptive lymphocytes. However, the IL-17 family has widespread expression throughout evolution, dating as far back as cnidaria, molluscs and worms, which predate lymphocytes. The evolutionary conservation of IL-17 suggests that it is involved in innate defence strategies, but also that this cytokine family has a fundamental role beyond typical host defence. Throughout evolution, IL-17 seems to have a major function in homeostatic maintenance at barrier sites. Most recently, a pivotal role has been identified for IL-17 in regulating cellular metabolism, neuroimmunology and tissue physiology, particularly in adipose tissue. Here we review the emerging role of IL-17 signalling in regulating metabolic processes, which may shine a light on the evolutionary role of IL-17 beyond typical immune responses. We propose that IL-17 helps to coordinate the cross-talk among the nervous, endocrine and immune systems for whole-body energy homeostasis as a key player in neuroimmunometabolism.

DOI: https://doi.org/10.1038/s42255-023-00846-3

Diabetes Metab J. 2023 Jul 24.

Adipose Tissue and Metabolic Health.

Sung-Min An, Seung-Hee Cho, John C Yoon.

In this review, we provide a brief synopsis of the connections between adipose tissue and metabolic health and highlight some recent developments in understanding and exploiting adipocyte biology. Adipose tissue plays critical roles in the regulation of systemic glucose and lipid metabolism and secretes bioactive molecules possessing endocrine, paracrine, and autocrine functions. Dysfunctional adipose tissue has a detrimental impact on metabolic health and is intimately involved in key aspects of metabolic diseases such as insulin resistance, lipid overload, inflammation, and organelle stress. Differences in the distribution of fat depots and adipose characteristics relate to divergent degrees of metabolic dysfunction found in metabolically healthy and unhealthy obese individuals. Thermogenic adipocytes increase energy expenditure via mitochondrial uncoupling or adenosine triphosphate-consuming futile substrate cycles, while functioning as a metabolic sink and participating in crosstalk with other metabolic organs. Manipulation of adipose tissue provides a wealth of opportunities to intervene and combat the progression of associated metabolic diseases. We discuss current treatment modalities for obesity including incretin hormone analogs and touch upon emerging strategies with therapeutic potential including exosome-based therapy, pharmacological activation of brown and beige adipocyte thermogenesis, and administration or inhibition of adipocyte-derived factors.

Keywords: Adipose tissue; Inflammation; Metabolism; Obesity; Thermogenesis

DOI: https://doi.org/10.4093/dmj.2023.0011

Res Sq. 2023 Jul 13. pii: rs.3.rs-3097605. [Epub ahead of print]

A single nuclei atlas of aging human abdominal subcutaneous white adipose tissue.

Lauren Sparks, Katie Whytock, Adeline Divoux, Yifei Sun, Maria Pino, Gongxin Yu, Steven Smith, Martin Walsh.

White adipose tissue (WAT) is a robust energy storage and endocrine organ critical for maintaining metabolic health as we age. Our aim was to identify cell-specific transcriptional aberrations that occur in WAT with aging. We leveraged full-length snRNA-Seq to characterize the cellular landscape of human subcutaneous WAT in a prospective cohort of 10 Younger (≤ 30 years) and 10 Older individuals (≥ 65 years) balanced for sex and body mass index (BMI). We highlight that aging WAT is associated with adipocyte hypertrophy, increased proportions of resident macrophages (M2), an upregulated innate immune response and senescence profiles in specific adipocyte populations, highlighting CXCL14 as a biomarker of this process. We also identify novel markers of pre-adipocytes and track their expression levels through pre-adipocyte differentiation. We propose that aging WAT is associated with low-grade inflammation that is managed by a foundation of innate immunity to preserve the metabolic health of the WAT.

DOI: https://doi.org/10.21203/rs.3.rs-3097605/v1

Nature. 2023 Jul 26.

Mammary duct luminal epithelium controls adipocyte thermogenic programme.

Sympathetic activation during cold exposure increases adipocyte thermogenesis via the expression of mitochondrial protein uncoupling protein 1 (UCP1)1. The propensity of adipocytes to express UCP1 is under a critical influence of the adipose microenvironment and varies between sexes and among various fat depots2-7. Here we report that mammary gland ductal epithelial cells in the adipose niche regulate cold-induced adipocyte UCP1 expression in female mouse subcutaneous white adipose tissue (scWAT). Single-cell RNA sequencing shows that glandular luminal epithelium subtypes express transcripts that encode secretory factors controlling adipocyte UCP1 expression under cold conditions. We term these luminal epithelium secretory factors 'mammokines'. Using 3D visualization of whole-tissue immunofluorescence, we reveal sympathetic nerve-ductal contact points. We show that mammary ducts activated by sympathetic nerves limit adipocyte UCP1 expression via the mammokine lipocalin 2. In vivo and ex vivo ablation of mammary duct epithelium enhance the cold-induced adipocyte thermogenic gene programme in scWAT. Since the mammary duct network extends throughout most of the scWAT in female mice, females show markedly less scWAT UCP1 expression, fat oxidation, energy expenditure and subcutaneous fat mass loss compared with male mice, implicating sex-specific roles of mammokines in adipose thermogenesis. These results reveal a role of sympathetic nerve-activated glandular epithelium in adipocyte UCP1 expression and suggest that mammary duct luminal epithelium has an important role in controlling glandular adiposity.

DOI: https://doi.org/10.1038/s41586-023-06361-5

Nat Aging. 2023 Jul 24.

Impaired BCAA catabolism in adipose tissues promotes age-associated metabolic derangement.

Hye-Sook Han, Eunyong Ahn, Eun Seo Park, Tom Huh, Seri Choi, Yongmin Kwon, Byeong Hun Choi, Jueun Lee, Yoon Ha Choi, Yujin L Jeong, Gwang Bin Lee, Minji Kim, Je Kyung Seong, Hyun Mu Shin, Hang-Rae Kim, Myeong Hee Moon, Jong Kyoung Kim, Geum-Sook Hwang, Seung-Hoi Koo.

Adipose tissues are central in controlling metabolic homeostasis and failure in their preservation is associated with age-related metabolic disorders. The exact role of mature adipocytes in this phenomenon remains elusive. Here we describe the role of adipose branched-chain amino acid (BCAA) catabolism in this process. We found that adipocyte-specific Crtc2 knockout protected mice from age-associated metabolic decline. Multiomics analysis revealed that BCAA catabolism was impaired in aged visceral adipose tissues, leading to the activation of mechanistic target of rapamycin complex (mTORC1) signaling and the resultant cellular senescence, which was restored by Crtc2 knockout in adipocytes. Using single-cell RNA sequencing analysis, we found that age-associated decline in adipogenic potential of visceral adipose tissues was reinstated by Crtc2 knockout, via the reduction of BCAA-mTORC1 senescence-associated secretory phenotype axis. Collectively, we propose that perturbation of BCAA catabolism by CRTC2 is critical in instigating age-associated remodeling of adipose tissue and the resultant metabolic decline in vivo.

DOI: https://doi.org/10.1038/s43587-023-00460-8

Cell Rep. 2023 Jul 19. pii: S2211-1247(23)00825-2. [Epub ahead of print] 112814

CD4+ T cells regulate sickness-induced anorexia and fat wasting during a chronic parasitic infection.

Samuel E Redford, Siva Karthik Varanasi, Karina K Sanchez, Natalia R Thorup, Janelle S Ayres.

Infections cause catabolism of fat and muscle stores. Traditionally, studies have focused on understanding how the innate immune system contributes to energy stores wasting, while the role of the adaptive immune system remains elusive. In the present study, we examine the role of the adaptive immune response in adipose tissue wasting and cachexia using a murine model of the chronic parasitic infection Trypanosoma brucei, the causative agent of sleeping sickness. We find that the wasting response occurs in two phases, with the first stage involving fat wasting caused by CD4+ T cell-induced anorexia and a second anorexia-independent cachectic stage that is dependent on CD8+ T cells. Fat wasting has no impact on host antibody-mediated resistance defenses or survival, while later-stage muscle wasting contributes to disease-tolerance defenses. Our work reveals a decoupling of adaptive immune-mediated resistance from the catabolic response during infection.

Keywords: CD4+ T cell; CD8+ T cell; CP: Immunology; T. brucei; adaptive immunity; adipose tissue wasting; anorexia; cachexia; disease tolerance

DOI: https://doi.org/10.1016/j.celrep.2023.112814