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

J Physiol. 2022 Oct;600(20):4485-4501. doi: 10.1113/JP283684. Epub 2022 Sep 20.


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.

Keywords: glucose homeostasis; immunometabolism; insulin resistance; macrophage; obesity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Diet, High-Fat* / adverse effects
  • Exons
  • Fatty Acids / metabolism
  • Female
  • Glucose / metabolism
  • Insulin / metabolism
  • Insulin Resistance*
  • Lipids
  • Male
  • Membrane Glycoproteins* / genetics
  • Membrane Glycoproteins* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Obesity / genetics
  • Obesity / metabolism
  • Receptors, Immunologic* / genetics
  • Receptors, Immunologic* / metabolism
  • Triglycerides / metabolism


  • Fatty Acids
  • Insulin
  • Lipids
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Trem2 protein, mouse
  • Triglycerides
  • Glucose