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Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
Published on: April 3, 2017
Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to
Laurent L'homme1, Benan Pelin Sermikli2, Joel T Haas2
1Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France. laurent.l-homme@inserm.fr.
Abstract:
Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15. Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels.
Insights
Plasma growth differentiation factor-15 (GDF-15) rises with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Adipose tissue and liver are key sources, with macrophages driving early GDF-15 production in obesity and type 2 diabetes.
Area of Science:
- Metabolic disease research
- Immunology
- Hepatology
Background:
- Plasma growth differentiation factor-15 (GDF-15) levels are elevated in obesity and metabolic dysfunction-associated steatotic liver disease (MASLD).
- The precise mechanisms driving GDF-15 elevation in these conditions are not fully understood.
Purpose of the Study:
- To elucidate the cellular sources and regulatory mechanisms of GDF-15 production in obesity, type 2 diabetes (T2D), and MASLD.
- To investigate the role of GDF-15 in the pathogenesis of these metabolic diseases.
Main Methods:
- Utilized male mouse models of obesity and MASLD.
- Analyzed patient biopsies from individuals with varying obesity, T2D, and MASLD status.
- Investigated GDF-15 expression in adipose tissue and liver, focusing on immune cell infiltration and specific signaling pathways (TFEB, DDIT3).
- Employed genetic inactivation of Gdf15 in macrophages.
Main Results:
- Adipose tissue (AT) is identified as the primary source of GDF-15 during the onset of obesity and T2D, largely due to macrophage accumulation.
- Liver GDF-15 production increases during the progression to metabolic dysfunction-associated steatohepatitis (MASH).
- Macrophage-specific Gdf15 inactivation in mice led to decreased plasma GDF-15 and exacerbated obesity.
- Hepatocyte GDF-15 expression in MASH is regulated by stress-induced TFEB and DDIT3 signaling.
Conclusions:
- Adipose tissue and liver exhibit a dual role in GDF-15 production during metabolic diseases.
- Macrophages are critical for early GDF-15 elevation in obesity and T2D.
- Targeting GDF-15 production in AT and liver may offer therapeutic strategies for metabolic dysfunction.
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