Alterations in Human Visceral Adipose Tissue Type 2 Innate Lymphoid Cells (ILC2s) with Aging: A Determinant of Insulin Resistance

Background: The obese adipose tissue (AT) immune cell microenvironment contributes to low-grade inflammation increasing the risk of multiple metabolic complications. Type 2 innate lymphoid cells (ILC2s) were recently discovered in mice to regulate metabolic health, but the clinical relevance of ILC2s in human AT is unknown. Rationale: Our goals were to characterize changes human AT ILC2s in obesity, insulin resistance, and aging. We further examined changes in AT ILC2s with aging, high fat diet (HFD), and weight loss in mice. Methods: We collected visceral AT (VAT) biopsies from 50 obese and 9 lean patients during elective surgery, isolated the adipocytes from the stromal vascular fraction, and performed flow cytometry. Results: Human VAT %ILC2s were not different between lean and obese subjects (p=0.896), but were negatively associated with insulin sensitivity (r=-0.449, p=0.005), beta-cell function (r=-0.364, p=0.024), and increasing age (r=-0.337, p=0.012). ILC2s were also positively associated with T helper type 2 cells (Th2s). All of these relationships were independent of BMI and gender, suggesting that ILC2s play a weight-independent role in human glucose homeostasis and age-related insulin resistance, possibly through an interaction with Th2s. When placed on HFD for 6 and 12 weeks, mice demonstrated a depletion in VAT ILC2s, and 12- vs. 3-month old mice had decreased VAT ILC2s, which did not recover after 12 weeks of weight loss despite normalization of body weight. Conclusions: In humans and mice, VAT ILC2s decrease with HFD and age. In humans ILC2s may be a weight-independent determinant of hyperinsulinemia and insulin resistance, provide a potential link to reduced insulin sensitivity in aging, and offer a novel therapeutic target in insulin resistance and T2D. Disclosure D. Bradley: None. A.M. Blaszczak: None. J.Z. Liu: None. A.D. Jalilvand: None. V.P. Wright: None. S. Noria: None. J. Joseph: None. W. Hsueh: None. Funding American Diabetes Association (1-16-ICTS-049 to W.H.); National Institutes of Health (KL2TR001068, HL135622)