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.
In the setting of obesity and insulin resistance, glycemia is controlled in part by beta cell compensation and subsequent hyperinsulinemia. Weight loss improves glycemia and decreases hyperinsulinemia, whereas weight cycling worsens glycemic control. The mechanisms responsible for weight cycling-induced deterioration in glucose homeostasis are poorly understood. Thus, we aimed to pinpoint the main regulatory junctions at which weight cycling alters glucose homeostasis in mice. Using in vivo and ex vivo procedures we show that despite having worsened glucose tolerance, weight-cycled mice do not manifest impaired whole-body insulin action. Instead, weight cycling reduces insulin secretory capacity in vivo during clamped hyperglycemia and ex vivo in perifused islets. Islets from weight-cycled mice have reduced expression of factors essential for β-cell function (Mafa, Pdx1, Nkx6.1, Ucn3) and lower islet insulin content, compared to those from obese mice, suggesting inadequate transcriptional and posttranscriptional response to repeated nutrient overload. Collectively, these data support a model in which pancreatic plasticity is challenged in the face of large fluctuations in body weight resulting in a mismatch between glycemia and insulin secretion in mice.
Purpose of Review In this review, we focus on immune cell activation in obesity and cardiovascular disease, highlighting specific immune cell microenvironments present in individuals with atherosclerosis, non-ischemic heart disease, hypertension, and infectious diseases. Recent Findings Obesity and cardiovascular disease are intimately linked and often characterized by inflammation and a cluster of metabolic complications. Compelling evidence from single-cell analysis suggests that obese adipose tissue is inflammatory and infiltrated by almost all immune cell populations. How this inflammatory tissue state contributes to more systemic conditions such as cardiovascular and infectious disease is less well understood. However, current research suggests that changes in the adipose tissue immune environment impact an individual’s ability to combat illnesses such as influenza and SARS-CoV2 . Summary Obesity is becoming increasingly prevalent globally and is often associated with type 2 diabetes and heart disease. An increased inflammatory state is a major contributor to this association. Widespread chronic inflammation in these disease states is accompanied by an increase in both innate and adaptive immune cell activation. Acutely, these immune cell changes are beneficial as they sustain homeostasis as inflammation increases. However, persistent inflammation subsequently damages tissues and organs throughout the body. Future studies aimed at understanding the unique immune cell populations in each tissue compartment impacted by obesity may hold potential for therapeutic applications.
<p>In the setting of obesity and insulin resistance, glycemia is controlled in part by beta cell compensation and subsequent hyperinsulinemia. Weight loss improves glycemia and decreases hyperinsulinemia, whereas weight cycling worsens glycemic control. The mechanisms responsible for weight cycling-induced deterioration in glucose homeostasis are poorly understood. Thus, we aimed to pinpoint the main regulatory junctions at which weight cycling alters glucose homeostasis in mice. Using <em>in vivo</em> and <em>ex vivo</em> procedures we show that despite having worsened glucose tolerance, weight-cycled mice do not manifest impaired whole-body insulin action. Instead, weight cycling reduces insulin secretory capacity <em>in vivo</em> during clamped hyperglycemia and <em>ex vivo</em> in perifused islets. Islets from weight-cycled mice have reduced expression of factors essential for b-cell function (<em>Mafa</em>, <em>Pdx1</em>, <em>Nkx6.1, Ucn3</em>) and lower islet insulin content, compared to those from obese mice, suggesting inadequate transcriptional and posttranscriptional response to repeated nutrient overload. Collectively, these data support a model in which pancreatic plasticity is challenged in the face of large fluctuations in body weight resulting in a mismatch between glycemia and insulin secretion in mice </p>
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-/-) has been implicated in evoking adipose tissue dysfunction, but its role in worsening obesity-induced metabolic dysfunction is not 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 WT and Trem2-/- mice were fed low fat 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 prior 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) or when animals were challenged with a non-lethal dose of endotoxin. Collectively, we report a disassociation between adipose tissue remodeling 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.