Role of Macrophage-Derived Progranulin in Energy and Glucose Metabolism

Do Kyeong Song

doi:10.4093/dmj.2025.0478

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Editorial Role of Macrophage-Derived Progranulin in Energy and Glucose Metabolism: Do Kyeong Song; Diabetes & Metabolism Journal 2025;49(4):580-581.
DOI: https://doi.org/10.4093/dmj.2025.0478
Published online: July 1, 2025

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Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea

Corresponding author: Do Kyeong Song

Department of Internal Medicine, Ewha Womans University College of Medicine, 25 Magokdong-ro 2-gil, Gangseo-gu, Seoul 07804, Korea E-mail: dksong@ewha.ac.kr

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Obesity affects the health of multiple organ systems and is linked to several diseases, including type 2 diabetes mellitus. Previous studies have revealed a close relationship between nutrient excess and inflammation as potential mechanisms underlying the pathogenesis of obesity-related diseases [1]. The hypothalamus plays a critical role in integrating metabolic feedback and regulating energy homeostasis. There is increasing evidence that hypothalamic inflammation is associated with the onset and progression of obesity and contributes to the insulin resistance associated with obesity. Chronic overnutrition induces a persistent inflammatory process in the hypothalamus through interactions between neuronal and nonneuronal cell populations. Microglia, astrocytes, perivascular macrophages, and infiltrating immune cells release proinflammatory cytokines, impairing neuronal function and altering feeding behavior and energy expenditure [2]. Adipocytes also play important roles in sensing and managing energy status. Adipose tissue responds to overnutrition through an immune response, and inflammation induces insulin resistance through various molecular mechanisms [3].

Progranulins (PGRNs) are a group of secreted proteins encoded by the granulin gene (Grn). PGRNs have polymorphic properties, but their exact role is unclear, although they play important roles in the homeostatic dynamics of normal tissue development, proliferation, and regeneration. These proteins are expressed in epithelial cells, neurons, and macrophages and are gaining attention because of their crucial role in immune modulation in various inflammatory contexts [4]. In research using PGRN-expressing adenoviruses, PGRN was shown to have protective effects against hepatic inflammation and fibrosis [5]. Inhibition of hypothalamic PGRN has been linked to increased food intake and weight gain, and alterations in hypothalamic PGRN might be associated with appetite dysregulation in obesity [6].

Previous studies involving Grn-knockout mice have reported conflicting results. Mice with global knockout of Grn (Grn^−/−) exhibit attenuated high-fat diet (HFD)-induced insulin resistance, adipocyte hypertrophy, and obesity [7]. Mutations in the PGRN gene have been reported to cause frontotemporal dementia. PGRN-deficient mice exhibit an exaggerated inflammatory response to infection, and PGRN-deficient macrophages produce higher levels of proinflammatory cytokines [8]. PGRN deficiency results in excessive cholesterol accumulation in macrophages and alterations in high-density lipoprotein-related proteins. PGRN might be involved in the pathogenesis of atherosclerosis through various mechanisms, including the suppression of inflammation and the maintenance of intracellular cholesterol homeostasis [9]. The total range of functions of PGRN is unknown and requires further investigation, especially in drug development targeting obesity and obesity-related metabolic complications.

It is unclear which cell type-derived PGRN plays a role in the development of insulin resistance and obesity and the specific role of macrophage-derived PGRN in homeostatic regulation of energy and glucose metabolism. A recent study by Lee et al. [10] revealed that macrophage Grn deficiency recapitulates the metabolic phenotype observed in Grn^−/− mice and significantly improves inflammation and hormone signaling in both the hypothalamus and adipose tissues. Considering the important role of macrophages in HFD-induced obesity and inflammation, researchers have bred mice with macrophage-specific Grn deficiency (Grn-MΦKO mice) by crossing lysozyme M (LysM)-Cre mice with Grn-floxed mice. Specific Grn depletion in macrophages affects energy and glucose metabolism in a diet-dependent manner. Macrophage-specific Grn deficiency ameliorates the development of obesity and glucose dysregulation under HFD conditions but not under normal diet conditions. HFD-induced macrophage activation and proinflammatory cytokine expression were significantly reduced in both the hypothalamus and adipose tissues of Grn-MΦKO mice. HFD-induced impairments in leptin and insulin signaling were ameliorated in Grn-MΦKO mice.

The important points of this paper are as follows. Macrophage-derived PGRN can play a major role in obesity development and metabolic complications under nutritional overload. Reduced inflammation and macrophage activation in visceral adipose tissues and the hypothalamus of Grn-MΦKO mice might underlie the role of PGRN in obesity. Researchers have also reported that macrophage PGRN plays a regulatory role in the polarization of adipose tissue macrophages, but the mechanism is unclear. Grn-MΦKO mice presented reduced activation of microglia and astrocytes and decreased expression of proinflammatory cytokines in the hypothalamus. Macrophage PGRN or Grn-derived peptides can impede insulin sensitivity in the adipocytes of diet-induced obese (DIO) mice. Similarly, macrophage PGRN appears to impair leptin sensitivity in hypothalamic neurons.

In conclusion, given that macrophages and their secreted molecules can influence obesity and its metabolic complications, Lee et al. [10] aimed to better understand the role of macrophage-derived PGRN in the homeostatic regulation of energy and glucose metabolism. Macrophage-derived PGRN was a significant contributor to metabolic inflammation and dysregulation during DIO progression. Because of the complex role of PGRN, further studies are needed to elucidate how PGRN and other Grn-derived peptides affect energy and glucose metabolism and the detailed mechanisms by which PGRN regulates insulin and leptin signaling.

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No potential conflict of interest relevant to this article was reported.

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