Circulating sex steroids coregulate adipose tissue immune cell populations in healthy men

Abstract

Male hypogonadism results in changes in body composition characterized by increases in fat mass. Resident immune cells influence energy metabolism in adipose tissue and could promote increased adiposity through paracrine effects. We hypothesized that manipulation of circulating sex steroid levels in healthy men would alter adipose tissue immune cell populations. Subjects ( = 44 men, 19-55 yr of age) received 4 wk of treatment with the gonadotropin-releasing hormone receptor antagonist acyline with daily administration of ) placebo gel,) 1.25 g testosterone gel (1.62%), ) 5 g testosterone gel, or) 5 g testosterone gel with an aromatase inhibitor. Subcutaneous adipose tissue biopsies were performed at baseline and end-of-treatment, and adipose tissue immune cells, gene expression, and intra-adipose estrogen levels were quantified. Change in serum total testosterone level correlated inversely with change in the number of CD3 (β = -0.36, = 0.04), CD4 (β = -0.34, = 0.04), and CD8 (β = -0.33, = 0.05) T cells within adipose tissue. Change in serum 17β-estradiol level correlated inversely with change in the number of adipose tissue macrophages (ATMs) (β = -0.34, = 0.05). A negative association also was found between change in serum testosterone and change in CD11c ATMs (β = -0.41, = 0.01). Overall, sex steroid deprivation was associated with increases in adipose tissue T cells and ATMs. No associations were found between changes in serum sex steroid levels and changes in adipose tissue gene expression. Circulating sex steroid levels may regulate adipose tissue immune cell populations. These exploratory findings highlight a possible novel mechanism that could contribute to increased metabolic risk in hypogonadal men.

Interactions Between the Neuroendocrine System and T Lymphocytes in Diabetes

“…Recently, Rubinow and colleagues analyzed lymphocyte subsets in subcutaneous adipose tissue biopsies after 4 weeks of pharmacological testosterone suppression with a GnRH receptor antagonist and controlled testosterone replacement in healthy male subjects. In this clinical study, change in serum total testosterone levels correlated inversely with CD3 + , CD4 + , and CD8 + T cells and ATMs within adipose tissue ( 275 ).…”

“…Estrogen protective action on glucose homeostasis is not only exerted in the pancreas; several studies indicated that estradiol enhances insulin sensitivity in peripheral tissues, improves body fat distribution, and reduces adipose tissue inflammation ( 273 – 275 ). Estrogen treatment prevented insulin insensitivity and reduced the expression of adipose tissue inflammation ( Mcp-1 and Cd68 ) induced by high-fat diet in ovariectomized mice ( 274 ).…”

An intracrine view of sex steroids, immunity, and metabolic regulation

“…Thus, in obese men and women, no correlation was found between 17β-estradiol concentrations in plasma and visceral fat, and disproportionately elevated estradiol concentrations were found in adipose tissue relative to plasma in obese men [89] . Dissociations also were found between plasma and breast fatty tissue estrogen concentrations in women as well as plasma and subcutaneous adipose tissue estrogen concentrations in healthy men subject to experimental sex steroid manipulation [12] , [90] . Consequently, understanding the metabolic roles of sex steroid immunomodulation requires quantification of local, tissue-specific sex steroid concentrations, identification of the key cell types implicated in local sex steroid production, and delineation of the pathways that regulate sex steroid synthesis and metabolism within metabolic tissues.…”

The Effects of Androgens on T Cells: Clues to Female Predominance in Autoimmune Liver Diseases?

“…Therefore, androgens may already influence the frequencies of T cells in vivo early in life. In adult men, there is a recent report of a negative correlation between CD3+, CD8+, and CD4+ T cells residing in adipose tissue and serum testosterone levels ( 69 ). Moreover, upon stimulation of healthy human PBMC with TLR8/9 ligands, secretion of IL-10 in male PBMC was higher than in female PBMC.…”