Adipose tissue microenvironments during aging: Effects on stimulated lipolysis

Abstract

Adipose tissue is a critical organ for nutrient sensing, energy storage and maintaining metabolic health. The failure of adipose tissue homeostasis leads to metabolic disease that is seen during obesity or aging. Local metabolic processes are coordinated by interacting microenvironments that make up the complexity and heterogeneity of the adipose tissue. Catecholamine-induced lipolysis, a critical pathway in adipocytes that drives the release of stored triglyceride as free fatty acid after stimulation, is impaired during aging. The impairment of this pathway is associated with a failure to maintain a healthy body weight, core body-temperature during cold stress or mount an immune response. Along with impairments in aged adipocytes, aging is associated with an accumulation of inflammation, immune cell activation, and increased dysfunction in the nervous and lymphatic systems within the adipose tissue. Together these microenvironments support the initiation of stimulated lipolysis and the transport of free fatty acid under conditions of metabolic homeostasis. However, during aging, the defects in these cellular systems result in a reduction in ability to stimulate lipolysis. This review will focus on how the immune, nervous and lymphatic systems interact during tissue homeostasis, review areas that are impaired with aging and discuss areas of research that are currently unclear.

Keywords: Adipose tissue lipolysis; Aging; Immune cells; Inflammation; Lymphatic vessels; Sympathetic nervous system.

Figure 1.. Interactions within aged adipose tissue.

Schematic shows major cell types and interactions within aged adipose tissue that drive catecholamine-impaired lipolysis. Letters indicate interacting microenvironments within adipose tissue. A. Adipocytes induce lipase activation and hydrolysis of triglycerides in response to catecholamines (norepinephrine: NE) that signal through β-adrenergic (β-AR) receptors. Details of β-AR signaling described in the text (2.2). This pathway is reduced during aging, in part due to changes within adipocytes, but also due to altered interactions in the aged tissue. B. Macrophages are found throughout the tissue, including lining sympathetic nerves. Macrophages drive inflammaging in adipose tissue, contributing to tissue dysfunction. Macrophages may also degrade catecholamines or take-up lipid which directly impairs the lipolysis pathway. C. Lymphatic vessels maintain fluid homeostasis. Lymph flow and contractions are reduced, while permeability is increased, indicating that lymph accumulation can occur throughout adipose tissue. Lymph contains damage associated molecular products (DAMPs), cholesterol, fatty acid, antigen that induce adipogenesis, inflammation and senescence. Dendritic cells interaction with lymphatic vessels control their permeability. D. Fat-associated lymphoid clusters, containing B and T cells, accumulate in aged adipose tissue on lymphatic vessels, potentially a result of accumulating DAMPs in lymph. The direct connection is unknown, but aged adipose B cells inhibit lipolysis, possibly because of their close contact with adipocytes and lymphatic vessels. ATGL: adipocyte triglyceride lipase; HSL: hormone sensitive lipase; TAG: triacylglyceride; FFA: free fatty acid; FALC; fat-associated lymphoid cluster.

Figure 2.. Adipose tissue immune cells are altered with age.

Schematic to describe the changes in adipose tissue immune cells with age. CD4 T cells and CD8 T cells accumulate in aged tissue, but less is known about their function. The changes in myeloid cells, including eosinophils and macrophages, and B cells are well-described and illustrated here. Macrophages (Mac) in young mice are anti-inflammatory and they become more inflammatory with age. Eosinophils (Eo) are abundant in young healthy tissue, secreting IL-4 to maintain anti-inflammatory macrophages and B regulatory B cells. B1 cells secreting IgM are also present in adipose tissue. With age, there is a reduction in Eo, and expansion in T cells (top) and B cells (bottom). Multiple subsets of B cells are expanded including B2, B1 and plasma cells.

Figure 3.. Age-induced changes in systems within white adipose tissue (WAT) coordinately drive impaired stimulated lipolysis.

Schematic to describe the known factors and unknown factors in the various systems that may contribute to impaired white adipose tissue lipolysis. Tyrosine hydroxylase: TH; Norephinephrine: NE; Fat-associated lymphoid cluster: FALC; β-Adrenergic Receptor: β-AR; Hormone sensitive lipase: HSL; Stimulated: Stim.; Free fatty acid: FFA; Antibodies: Abs; White adipose tissue (WAT).