LIFR-α-dependent adipocyte signaling in obesity limits adipose expansion contributing to fatty liver disease

Guo, Tong; Gupta, A.; Yu, Jinhai; Granados, Jorge; Gandhi, Aakash Y.; Evers, B. Mark; Iyengar, Puneeth; Infante, Rodney E.

doi:10.1016/j.isci.2021.102227

Cited by 15 publications

(16 citation statements)

References 40 publications

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“…Cachexia is observed in 50% of all solid tumor patients, responsible for 30% of all cancer-related deaths, and ultimately an independent risk factor for reduced cancer-specific mortality ( 1 , 4 ). Obesity, a disease of adipose excess, represents the opposite end of the metabolic spectrum from cachexia with net increases in adipose triglyceride content while still associated with similar cytokine profiles and signaling events in adipose tissue ( 5 – 7 ). Obesity is a significant risk factor in the development of metabolic syndrome and cancer development, affecting morbidity and mortality in 1/3 of the world’s population.…”

Section: Introductionmentioning

confidence: 99%

Cytokine-Mediated STAT3 Transcription Supports ATGL/CGI-58-Dependent Adipocyte Lipolysis in Cancer Cachexia

Gandhi

Gupta

et al. 2022

Front. Oncol.

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Adipose tissue inflammation is observed in multiple metabolically-altered states including cancer-associated cachexia and obesity. Although cachexia is a syndrome of adipose loss and obesity is a disease of adipose excess, both pathologies demonstrate increases in circulating levels of IL-6 family cytokines, β-adrenergic signaling, and adipocyte lipolysis. While β-adrenergic-stimulated adipocyte lipolysis is well described, there is limited mechanistic insight into how cancer cachexia-associated inflammatory cytokines contribute to adipocyte lipolysis under pathologic conditions. Here, we set out to compare adipocyte lipolysis signaling by cancer cachexia-associated IL-6 family cytokines (IL-6 and LIF) to that of the β-adrenergic agonist isoproterenol. Unlike isoproterenol, the IL-6 family of cytokines required JAK/STAT3-dependent transcriptional changes to induce adipocyte lipolysis. Furthermore, cachexia-associated cytokines that used STAT3 to induce lipolysis were primarily dependent on the lipase ATGL and its cofactor CGI-58 rather than lipases HSL and MAGL. Finally, administration of JAK but not β-adrenergic inhibitors suppressed adipose STAT3 phosphorylation and associated adipose wasting in a murine model of cancer cachexia characterized by increased systemic IL-6 family cytokine levels. Combined, our results demonstrate how the IL-6 family of cytokines diverge from β-adrenergic signals by employing JAK/STAT3-driven transcriptional changes to promote adipocyte ATGL/CGI-58-dependent lipolysis contributing to adipose wasting in cancer cachexia.

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Section: Introductionmentioning

confidence: 99%

Cytokine-Mediated STAT3 Transcription Supports ATGL/CGI-58-Dependent Adipocyte Lipolysis in Cancer Cachexia

Gandhi

Gupta

et al. 2022

Front. Oncol.

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“…In mice and humans, increased IFI16 levels are associated with larger adipocytes, enhanced inflammatory state, and impaired insulin-stimulated glucose uptake in white adipose tissue [ 78 ]. STAT3 is a relevant transcription factor of proinflammatory genes in adipocytes that is associated with adipocyte inflammation [ 79 , 80 ]. RELA is a relevant transcription factor associated with adipocyte inflammation [ 81 ] that inhibits adipogenesis and accumulation of lipids in adipocytes [ 82 ].…”

Section: Resultsmentioning

confidence: 99%

The Combined Partial Knockdown of CBS and MPST Genes Induces Inflammation, Impairs Adipocyte Function-Related Gene Expression and Disrupts Protein Persulfidation in Human Adipocytes

Latorre

Aroca²,

Fernández-Real³

et al. 2022

Antioxidants

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Recent studies in mice and humans demonstrated the relevance of H2S synthesising enzymes, such as CTH, CBS, and MPST, in the physiology of adipose tissue and the differentiation of preadipocyte into adipocytes. Here, our objective was to investigate the combined role of CTH, CBS, and MPST in the preservation of adipocyte protein persulfidation and adipogenesis. Combined partial CTH, CBS, and MPST gene knockdown was achieved treating fully human adipocytes with siRNAs against these transcripts (siRNA_MIX). Adipocyte protein persulfidation was analyzed using label-free quantitative mass spectrometry coupled with a dimedone-switch method for protein labeling and purification. Proteomic analysis quantified 216 proteins with statistically different levels of persulfidation in KD cells compared to control adipocytes. In fully differentiated adipocytes, CBS and MPST mRNA and protein levels were abundant, while CTH expression was very low. It is noteworthy that siRNA_MIX administration resulted in a significant decrease in CBS and MPST expression, without impacting on CTH. The combined partial knockdown of the CBS and MPST genes resulted in reduced cellular sulfide levels in parallel to decreased expression of relevant genes for adipocyte biology, including adipogenesis, mitochondrial biogenesis, and lipogenesis, but increased proinflammatory- and senescence-related genes. It should be noted that the combined partial knockdown of CBS and MPST genes also led to a significant disruption in the persulfidation pattern of the adipocyte proteins. Although among the less persulfidated proteins, we identified several relevant proteins for adipocyte adipogenesis and function, among the most persulfidated, key mediators of adipocyte inflammation and dysfunction as well as some proteins that might play a positive role in adipogenesis were found. In conclusion, the current study indicates that the combined partial elimination of CBS and MPST (but not CTH) in adipocytes affects the expression of genes related to the maintenance of adipocyte function and promotes inflammation, possibly by altering the pattern of protein persulfidation in these cells, suggesting that these enzymes were required for the functional maintenance of adipocytes.

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“…In support of this, we find that Empagliflozin increases nuchal white adipose tissue by decreasing nuchal brown fat depots ( Figure 9 ). Indeed, other studies have shown that increasing the capacity within this adipose depot correlates with diminished liver steatosis, independent of glucose and insulin tolerance [ 59 ]. Taken together, our data suggest that alteration of renal glucose handling promotes healthy adipose expansion thereby reducing lipid accumulation within tissues such as the visceral fat and liver, in the male TallyHo mice.…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, our data suggest that alteration of renal glucose handling promotes healthy adipose expansion thereby reducing lipid accumulation within tissues such as the visceral fat and liver, in the male TallyHo mice. This expansion has been linked to several signaling pathways including STAT3 and growth hormone receptor [ 55 , 59 , 60 ]. Clearly, future work is needed to determine if Empagliflozin, either directly or indirectly, influences these pathways that regulate expansion and white adipose lipogenesis.…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice

Kurtz

Libby

Jones

et al. 2022

IJMS

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Sodium-glucose co-transporters (SGLTs) serve to reabsorb glucose in the kidney. Recently, these transporters, mainly SGLT2, have emerged as new therapeutic targets for patients with diabetes and kidney disease; by inhibiting glucose reabsorption, they promote glycosuria, weight loss, and improve glucose tolerance. They have also been linked to cardiac protection and mitigation of liver injury. However, to date, the mechanism(s) by which SGLT2 inhibition promotes systemic improvements is not fully appreciated. Using an obese TallyHo mouse model which recapitulates the human condition of diabetes and nonalcoholic fatty liver disease (NAFLD), we sought to determine how modulation of renal glucose handling impacts liver structure and function. Apart from an attenuation of hyperglycemia, Empagliflozin was found to decrease circulating triglycerides and lipid accumulation in the liver in male TallyHo mice. This correlated with lowered hepatic cholesterol esters. Using in vivo MRI analysis, we further determined that the reduction in hepatic steatosis in male TallyHo mice was associated with an increase in nuchal white fat indicative of “healthy adipose expansion”. Notably, this whitening of the adipose came at the expense of brown adipose tissue. Collectively, these data indicate that the modulation of renal glucose handling has systemic effects and may be useful as a treatment option for NAFLD and steatohepatitis.

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LIFR-α-dependent adipocyte signaling in obesity limits adipose expansion contributing to fatty liver disease

Cited by 15 publications

References 40 publications

Cytokine-Mediated STAT3 Transcription Supports ATGL/CGI-58-Dependent Adipocyte Lipolysis in Cancer Cachexia

Cytokine-Mediated STAT3 Transcription Supports ATGL/CGI-58-Dependent Adipocyte Lipolysis in Cancer Cachexia

The Combined Partial Knockdown of CBS and MPST Genes Induces Inflammation, Impairs Adipocyte Function-Related Gene Expression and Disrupts Protein Persulfidation in Human Adipocytes

Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice

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