Introduction and Objective: Aging is the strongest risk factor for T2D, yet how age-dependent changes in energy-regulating tissues drive metabolic decline remains unclear. Brown adipose tissue (BAT) plays a role in adaptive thermogenesis and glucose metabolism, but whether aging alters BAT remodeling in a stage-dependent manner is unknown.Methods: We performed integrated metabolic phenotyping and single-cell profiling in young (8-week), mid-aged (75-week), and old (120-week) C57BL/6 mice. Whole-body energy expenditure was measured by indirect calorimetry at room temperature and cold exposure. Body composition was assessed by MRI. Glucose and insulin tolerance tests were performed. BAT depots were analyzed by histology, gene module analysis, and single-cell sequencing.Results: Aging led to progressive glucose intolerance; however, old mice unexpectedly exhibited enhanced insulin sensitivity compared to mid-aged animals, indicating dissociation between insulin action and glucose homeostasis. Cold exposure served as a physiologic BAT stress test. While mid-aged mice showed BAT remodeling characterized by adipocyte hypertrophy and partial thermogenic impairment, old mice exhibited reduced basal energy expenditure and blunted cold-induced thermogenic response. Histology revealed pronounced BAT whitening with lipid droplet enlargement in mid-aged mice, whereas old mice exhibited increased abundance of smaller lipid droplets, coinciding with enhanced insulin sensitivity. Transcriptomics showed reduced activation of thermogenic gene modules, increased stress-associated programs with advanced age, loss of adrenergically responsive thermogenic adipocyte states, and reduced progenitor and vascular support.Conclusion: BAT aging occurs as a progressive, stage-dependent process, transitioning from maladaptive remodeling at mid-age to failure of thermogenic adaptability in advanced age. This loss of BAT plasticity limits systemic metabolic flexibility and identifies a key mechanism linking aging to metabolic dysfunction.
H. Badr: None. A. Pavel: Research Support; Current; National Institute of Diabetes and Digestive and Kidney Diseases. N. Unsal: None. N. Rabhi: None.
National Institute of Diabetes, Digestive, and kidney diseases via the NIDDK via the NIDDK Information Network’s (dkNET) New Investigator Pilot Program in Bioinformatics (U24DK097771)
Source link
Leave a Reply