Myeloid GHSR Deficiency Protects Against Thermogenic Impairment in Aging Through Immune Remodeling of Brown Adipose Tissue

TL;DR

Deleting the GHSR receptor in immune cells improves cold tolerance and protects against age-related loss of body heat regulation.

Contribution

Myeloid GHSR deficiency is shown to protect against thermogenic impairment in aging through immune remodeling of brown fat.

Findings

Old mice with myeloid GHSR deletion showed preserved brown adipose tissue mass and improved cold tolerance.

Deletion of GHSR reduced pro-inflammatory markers and increased thermogenic gene expression in aged mice.

Macrophage GHSR drives age-related inflammation in brown fat, and its deletion promotes a favorable immune environment for thermogenesis.

Abstract

Thermoregulatory dysfunction is a major pathophysiological consequence of aging, affecting many elderly individuals. Growth hormone secretagogue receptor (GHSR) regulates energy homeostasis and immune function. We previously showed that global GHSR deletion improves thermogenic adaptation of brown adipose tissue (BAT) in aging, but the responsible cell type remained unclear. GHSR is expressed in macrophages, and its expression in macrophages increases with aging. Here, we studied myeloid-specific Ghsr-deleted male mice (LysM-Cre; Ghsrf/f denoted as “KO”) to assess their metabolic and immune responses to cold stress at young and old ages. Old mice showed impaired thermogenesis, marked by reduced core body temperature under 4 °C cold exposure, a blunted cold-induced increase in glucose levels, reduced BAT mass, and increased infiltration of pro-inflammatory CD38+ macrophages in BAT. In contrast, KO mice exhibited enhanced cold tolerance in both young and old mice. Notably, aged KO mice showed preserved BAT mass and a pronounced shift in resident macrophages toward an anti-inflammatory state. Consistently, aged KO mice showed reduced pro-inflammatory markers (Ccl2, Nos2) and increased expression of the thermogenic gene Ppargc1a and UCP1 protein under cold exposure. Together, these findings demonstrate that macrophage GHSR drives age-associated pro-inflammatory remodeling of BAT, and that its deletion promotes an immune environment favorable for thermogenic activation. Thus, targeting macrophage GHSR may offer a new therapeutic strategy to restore thermogenesis and enhance thermal resilience in aging.

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