Exon 2‐mediated deletion of Trem2 does not worsen metabolic function in diet‐induced obese mice

Abstract

Triggering receptor expressed on myeloid cells 2 (Trem2) is highly expressed on myeloid cells and is involved in cellular lipid homeostasis and inflammatory processes. Trem2 deletion in mice (Trem2−/−) evokes adipose tissue dysfunction, but its role in worsening obesity‐induced metabolic dysfunction has not been resolved. Here we aimed to determine the causal role of Trem2 in regulating glucose homeostasis and insulin sensitivity in mice. Nine‐week‐old male and female littermate wild‐type (WT) and Trem2−/− mice were fed a low‐ or high‐fat diet for 18 weeks and phenotyped for metabolic function. Diet‐induced weight gain was similar between genotypes, irrespective of sex. Consistent with previous reports, we find that loss of Trem2 causes massive adipocyte hypertrophy and an attenuation in the lipid‐associated macrophage transcriptional response to obesity. In contrast to published data, we find that loss of Trem2 does not worsen metabolic function in obese mice. No differences in intraperitoneal glucose tolerance (ipGTT), oral GTT or mixed meal substrate control, including postprandial glucose, non‐esterified fatty acids, insulin or triglycerides, were found between WT and Trem2−/− animals. Similarly, no phenotypic differences existed when animals were challenged with stressors on metabolic demand (i.e. acute exercise or environmental temperature modulation). Collectively, we report a disassociation between adipose tissue remodelling caused by loss of Trem2 and whole‐body metabolic homeostasis in obese mice. The complementary nature of experiments conducted gives credence to the conclusion that loss of Trem2 is unlikely to worsen glucose homeostasis in mice.

Trimming Trem2 and possible impacts on the metabolic syndrome

“…The discrepancies between the study by Winn et al. ( 2022 ) and previous studies may stem from genetic differences between the mouse strains used in these respective studies. Winn et al.…”

“…Alternatively, pharmacological inhibition via neutralizing antibodies (Park et al, 2015) or small molecules (Deczkowska et al, 2020) that modulate Trem2 signalling may provide insights into Trem2 function while avoiding genomic manipulations. The elegant study by Winn et al (2022) adds important insights into this quest, Perspective J Physiol 600.20 while highlighting the complexity and variability that are the hallmarks of metabolic phenotypes, which should be accounted for, in striving to develop effective metabolic interventions.…”

“…In this issue of The Journal of Physiology , Winn et al. ( 2022 ) aimed to reconcile some of these discrepancies. While they confirm that Trem2 ablation drives adipocyte hypertrophy and reduction in adipose tissue macrophages, as previously reported, they do not observe a Trem2 ‐dependent increase in body weight or adiposity under HFD or regular diet feeding.…”

“…Importantly, in an elegant set of stringent experiments, Winn et al. ( 2022 ) exclude the possibility that these conflicting results stem from differences in gender, routes of glucose administration (oral versus intraperitoneal), duration of fasting (5 versus 15 h), types of carbohydrate challenge (mixed meal versus glucose tolerance tests), duration of diet‐induced obesity (following HFD feeding for 12 or 16 weeks), and housing temperatures (22°C or 28°C). Under all of these conditions, and in contrast to previous observations (Jaitin et al., 2019 ; Liu et al., 2019 ; Sharif et al., 2021 ), Trem2 deletion neither impacted glucose tolerance, circulating insulin levels and glucose dispersion following insulin administration in an insulin tolerance test, nor did it affect exercise tolerance.…”

“…Based on their findings, Winn et al. ( 2022 ) conclude that Trem2 impacts adipose tissue remodelling, adipocyte size and accumulation of macrophages in adipose tissue during obesity; however, whole‐body loss of Trem2 is insufficient to disrupt systemic metabolic homeostasis.…”