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Altered microbiota by a high-fat diet accelerates lethal myeloid hematopoiesis associated with systemic SOCS3
Kaori Cho1, Takashi Ushiki1,2, Hajime Ishiguro1
1Department of Hematology, Endocrinology and Metabolism, Faculty of Medicine, Niigata University, Niigata, Niigata 951-8510, Japan.
Abstract:
The suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling required to prevent excessive cellular responses. In particular, SOCS3 is involved in the regulation of metabolic syndromes, such as obesity and diabetes, by suppressing leptin and insulin signals. SOCS3 also suppresses the inflammatory response associated with metabolic stress, but this specific role remains undefined. Wild-type mice on a high-fat diet (HFD) exhibited only fatty liver, whereas systemic deletion of SOCS3 resulted in excessive myeloid hematopoiesis and hepatic inflammation. In addition, depletion of the gut microbiota resulted in considerable improvement in excess granulopoiesis and splenomegaly, halting the progression of systemic inflammation in SOCS3KO mice on the HFD. This result suggests that intestinal dysbiosis is involved in inflammation associated with SOCS3KO. Although contributing to diet-induced obesity and fatty liver, SOCS3 is nevertheless critical to suppress excess myeloid hematopoiesis and severe systemic inflammation associated with intestinal dysbiosis on HFD.
Insights
Suppressors of cytokine signaling 3 (SOCS3) protein deficiency causes severe inflammation and myeloid issues in mice on a high-fat diet. Gut microbiota depletion mitigates these inflammation and hematopoiesis problems.
Area of Science:
- Immunology
- Metabolic Syndrome
- Microbiome Research
Background:
- Suppressors of cytokine signaling (SOCS) proteins, particularly SOCS3, are crucial negative regulators of cytokine signaling.
- SOCS3 plays a role in metabolic syndromes like obesity and diabetes by inhibiting leptin and insulin signaling.
- The precise function of SOCS3 in suppressing inflammation linked to metabolic stress is not fully understood.
Purpose of the Study:
- To investigate the specific role of SOCS3 in regulating inflammation during metabolic stress.
- To determine the impact of SOCS3 deficiency on myeloid hematopoiesis and hepatic inflammation in a high-fat diet model.
- To explore the potential involvement of gut microbiota in SOCS3-associated inflammation.
Main Methods:
- Utilized wild-type and SOCS3 knockout (SOCS3KO) mice fed a high-fat diet (HFD).
- Administered treatments to deplete gut microbiota in SOCS3KO mice on HFD.
- Monitored myeloid hematopoiesis, hepatic inflammation, splenomegaly, and systemic inflammation markers.
Main Results:
- Systemic deletion of SOCS3 in mice on HFD led to excessive myeloid hematopoiesis and hepatic inflammation, unlike wild-type mice with only fatty liver.
- Depletion of gut microbiota in SOCS3KO mice on HFD significantly reduced granulopoiesis and splenomegaly.
- Gut microbiota depletion halted the progression of systemic inflammation in SOCS3KO mice on HFD, suggesting a link between intestinal dysbiosis and inflammation.
Conclusions:
- SOCS3 is essential for suppressing excessive myeloid hematopoiesis and severe systemic inflammation.
- Intestinal dysbiosis is implicated in the inflammatory responses observed in SOCS3-deficient mice on a high-fat diet.
- While SOCS3 contributes to diet-induced obesity and fatty liver, its critical role lies in preventing inflammation exacerbated by gut dysbiosis.
