bims-adipim Biomed News
on Adipose immunity and immunometabolism
Issue of 2023‒04‒30
nine papers selected by
Matthew C. Sinton, University of Glasgow

  1. Curr Opin Genet Dev. 2023 Apr 22. pii: S0959-437X(23)00025-4. [Epub ahead of print]80 102045
      Adipose tissue is a heterogeneous organ, comprising cell types, including mature adipocytes, progenitor cells, immune cells, and vascular cells. Here, we discuss the heterogeneity of human and mouse white adipose tissue in general and white adipocytes specifically, focusing on how our understanding of adipocyte subpopulations has expanded with the advent of single nuclear RNA sequencing and spatial transcriptomics. Furthermore, we discuss critical remaining questions regarding how these distinct populations arise, how their functions differ from one another, and which potentially contribute to metabolic pathophysiology.
  2. Curr Opin Genet Dev. 2023 Apr 24. pii: S0959-437X(23)00026-6. [Epub ahead of print]80 102046
      The white adipose tissue's primary roles are to store and mobilise energy, which is very different from the brown adipose tissue's function of using fuel to generate heat and maintain the body temperature. The adipose tissues (ATs), co-ordinately with the other organs, sense energetic demands and inform of their reserves before embarking on energetically demanding physiological functions. It is not surprising that ATs exhibit highly integrated regulatory mechanisms mediated by a diversified secretome, including adipokines, lipokines, metabolites and a repertoire of extracellular miRNAs that contribute to integrating the function of the AT niche and connect the AT through paracrine and endocrine effects with the whole organism. Characterising the adipose secretome, its changes in health and disease, regulation by ageing and gender and their contribution to energy homoeostasis is necessary to optimise its use for personalised strategies to prevent or reverse metabolic diseases.
  3. Cell Rep. 2023 Apr 27. pii: S2211-1247(23)00451-5. [Epub ahead of print]42(5): 112440
      Elucidating the transitional stages that define the pathway stem cells progress through during differentiation advances our understanding of biology and fosters the identification of therapeutic opportunities. However, distinguishing progenitor cells from other cell types and placing them in an epistatic pathway is challenging. This is exemplified in the adipocyte lineage, where the stromal vascular fraction (SVF) from adipose tissue is enriched for progenitor cells but also contains heterogeneous populations of cells. Single-cell RNA sequencing (scRNA-seq) has begun to facilitate the deconvolution of cell types in the SVF, and a hierarchical structure is emerging. Here, we use scRNA-seq to discover a population of CD31- CD45- cells in the SVF that are distinguished by a specific expression profile. Further, we place this population on an epistatic pathway upstream of the previously defined preadipocyte population. Finally, we discover functional properties of this population with broad implications, including revealing physiological mechanisms that regulate adipogenesis.
    Keywords:  CD44; CP: Metabolism; CP: Stem cell research; Nocturnin; adipocyte progenitor cell; adipognesis; adipose
  4. Hum Cell. 2023 Apr 28.
      Metabolic and inflammatory pathways are highly interdependent, and both systems are dysregulated in Type 2 diabetes (T2D). T2D is associated with pre-activated inflammatory signaling networks, aberrant cytokine production and increased acute phase reactants which leads to a pro-inflammatory 'feed forward loop'. Nutrient 'excess' conditions in T2D with hyperglycemia, elevated lipids and branched-chain amino acids significantly alter the functions of immune cells including neutrophils. Neutrophils are metabolically active cells and utilizes energy from glycolysis, stored glycogen and β-oxidation while depending on the pentose phosphate pathway for NADPH for performing effector functions such as chemotaxis, phagocytosis and forming extracellular traps. Metabolic changes in T2D result in constitutive activation and impeded acquisition of effector or regulatory activities of neutrophils and render T2D subjects for recurrent infections. Increased flux through the polyol and hexosamine pathways, elevated production of advanced glycation end products (AGEs), and activation of protein kinase C isoforms lead to (a) an enhancement in superoxide generation; (b) the stimulation of inflammatory pathways and subsequently to (c) abnormal host responses. Neutrophil dysfunction diminishes the effectiveness of wound healing, successful tissue regeneration and immune surveillance against offending pathogens. Hence, Metabolic reprogramming in neutrophils determines frequency, severity and duration of infections in T2D. The present review discusses the influence of the altered immuno-metabolic axis on neutrophil dysfunction along with challenges and therapeutic opportunities for clinical management of T2D-associated infections.
    Keywords:  Immuno-metabolism; Infections; Metabolism; Neutrophil extracellular traps; Neutrophils; Type 2 diabetes
  5. PLoS One. 2023 ;18(4): e0285025
      In this study, we have compared frequencies, phenotype, function and metabolic requirements of B cells isolated from the breast and abdominal subcutaneous adipose tissue (AT) of women with obesity who underwent weight reduction surgeries. Results show that B cells from the abdominal AT are more inflammatory than those from the breast, characterized by higher frequencies of inflammatory B cell subsets and higher expression of RNA for inflammatory markers associated with senescence. Secretion of autoimmune antibodies is also higher in the abdominal AT as compared to the breast, and is associated with higher frequencies of autoimmune B cells with the membrane phenotype CD21lowCD95+ B cells expressing the transcription factor T-bet. Moreover, glucose uptake is higher in B cells from the abdominal AT as compared to the breast, thereby suggesting a better capacity to perform glycolysis, needed to support intrinsic B cell inflammation and autoimmune antibody secretion.
  6. Int J Mol Sci. 2023 Apr 11. pii: 7065. [Epub ahead of print]24(8):
      Leptin inhibits food intake and reduces the size of body fat depots, changing adipocyte sensitivity to insulin to restrain lipid accrual. This adipokine may modulate the production of cytokines that could diminish insulin sensitivity, particularly in visceral adipose tissue. To explore this possibility, we examined the effects of chronic central administration of leptin on the expression of key markers of lipid metabolism and its possible relationship with changes in inflammatory- and insulin-signaling pathways in epididymal adipose tissue. Circulating non-esterified fatty acids and pro- and anti-inflammatory cytokines were also measured. Fifteen male rats were divided into control (C), leptin (L, icv, 12 μg/day for 14 days), and pair-fed (PF) groups. We found a decrease in the activity of glucose-6-phosphate dehydrogenase and malic enzyme in the L group, with no changes in the expression of lipogenic enzymes. A reduction in the expression of lipoprotein lipase and carnitine palmitoyl-transferase-1A, together with a decrease in the phosphorylation of insulin-signaling targets and a low-grade inflammatory pattern, were detected in the epididymal fat of L rats. In conclusion, the decrease in insulin sensitivity and increased pro-inflammatory environment could regulate lipid metabolism, reducing epididymal fat stores in response to central leptin infusion.
    Keywords:  adipose tissue; cytokines; inflammation; insulin resistance; leptin; lipolysis
  7. Cell Rep. 2023 Apr 21. pii: S2211-1247(23)00426-6. [Epub ahead of print] 112415
      Crosstalk among organs/tissues is important for regulating systemic metabolism. Here, we demonstrate inter-organ crosstalk between hepatic insulin and hypothalamic leptin actions, which maintains survival during food shortages. In inducible liver insulin receptor knockout mice, body weight is increased with hyperphagia and decreased energy expenditure, accompanied by increased circulating leptin receptor (LepR) and decreased hypothalamic leptin actions. Additional hepatic LepR deficiency reverses these metabolic phenotypes. Thus, decreased hepatic insulin action suppresses hypothalamic leptin action with increased liver-derived soluble LepR. Human hepatic and circulating LepR levels also correlate negatively with hepatic insulin action indices. In mice, food restriction decreases hepatic insulin action and energy expenditure with increased circulating LepR. Hepatic LepR deficiency increases mortality with enhanced energy expenditure during food restriction. The liver translates metabolic cues regarding energy-deficient status, which is reflected by decreased hepatic insulin action, into soluble LepR, thereby suppressing energy dissipation and assuring survival during food shortages.
    Keywords:  CP: Metabolism; brown adipose tissue; energy expenditure; food intake; food restriction; insulin; insulin receptor; liver; soluble leptin receptor; survival; thermogenesis
  8. PLoS One. 2023 ;18(4): e0284012
      Cd248 has recently been associated with adipose tissue physiology, demonstrated by reduced weight gain in high fat diet-fed mice with genetic deletion of Cd248 relative to controls. Here we set out to determine the metabolic consequences of loss of Cd248. Strikingly, we find these to be sex specific; By subjecting Cd248-/- and Cd248+/+ mice to a high fat diet and indirect calorimetry study, we identified that only male Cd248-/- mice show reduced weight gain compared to littermate control wildtype mice. In addition, male (but not female) mice showed a lower respiratory exchange ratio on both chow and high fat diets, indicating a predisposition to metabolise lipid. Lipidomic studies on specific fat depots found reduced triglyceride and diglyceride deposition in male Cd248-/- mice, and this was supported by reduced expression of lipogenic and adipogenic genes. Finally, metabolomic analysis of isolated, differentiated preadipocytes found alterations in metabolic pathways associated with lipid deposition in cells isolated from male, but not female, Cd248-/- mice. Overall, our results highlight the importance of sex controls in animal studies and point to a role for Cd248 in sex- and depot-specific regulation of lipid metabolism.
  9. Elife. 2023 Apr 25. pii: e88080. [Epub ahead of print]12
      Caloric restriction (CR) is a nutritional intervention that reduces the risk of age-related diseases in numerous species, including humans. CR's metabolic effects, including decreased fat mass and improved insulin sensitivity, play an important role in its broader health benefits. However, the extent and basis of sex differences in CR's health benefits are unknown. We found that 30% CR in young (3-month-old) male mice decreased fat mass and improved glucose tolerance and insulin sensitivity, whereas these effects were blunted or absent in young female mice. Females' resistance to fat and weight loss was associated with decreased lipolysis, lower systemic energy expenditure and fatty acid oxidation, and increased postprandial lipogenesis compared to males. Positron emission tomography-computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) showed that peripheral glucose uptake was comparable between sexes. Instead, the sex differences in glucose homeostasis were associated with altered hepatic ceramide content and substrate metabolism: compared to CR males, CR females had lower TCA cycle activity but higher blood ketone concentrations, a marker of hepatic acetyl-CoA content. This suggests that males use hepatic acetyl-CoA for the TCA cycle whereas in females it accumulates, thereby stimulating gluconeogenesis and limiting hypoglycaemia during CR. In aged mice (18-months old), when females are anoestrus, CR decreased fat mass and improved glucose homeostasis to a similar extent in both sexes. Finally, in a cohort of overweight and obese humans CR-induced fat loss was also sex- and age-dependent: younger females (<45 years) resisted fat loss compared to younger males while in older subjects (>45 years) this sex difference was absent. Collectively, these studies identify age-dependent sex differences in the metabolic effects of CR and highlight adipose tissue, the liver and oestrogen as key determinants of CR's metabolic benefits. These findings have important implications for understanding the interplay between diet and health and for maximising the benefits of CR in humans.
    Keywords:  human; medicine