Biology subjects

Hasty, A. H.

Publications and source records attributed to Hasty, A. H..

8 recordsLinked to original sources

bioRxiv2026

Voluntary exercise during weight loss attenuates adipose CD8+ T cell exhaustion that persists after weight regain

BackgroundWeight gain and loss induce adipose CD8+ T cell exhaustion, which persists and may worsen glucose tolerance following weight regain. Because exercise can reduce T cell exhaustion in the blood, we hypothesized that exercise during weight loss would attenuate adipose CD8+ T cell exhaustion and glucose tolerance following weight regain. MethodsMale C57Bl/6J mice were fed low-fat or high-fat diets over 8 to 9-week cycles to generate lean, obese, weight loss, or weight cycled groups. Additional weight loss and weight cycled groups were provided exercise wheels during the weight loss phase. ResultsAs expected, weight loss increased total and exhausted CD8+ T cells by flow cytometry. Mice that ran the most during weight loss had the lowest proportion of exhausted CD8+ T cells. Notably, exercise reduced the proportion of exhausted CD8+ T cells even after the cessation of exercise and weight regain in all mice. However, exercise did not improve glucose tolerance or macrophage inflammation following weight regain. Moreover, exercise did not affect the induction of innate immune memory in adipose macrophages following weight loss. ConclusionThe addition of exercise to a weight loss intervention remarkably reduced exhausted CD8+ T cells in the adipose tissue even after the cessation of exercise and weight regain. While exercise did not affect macrophage inflammation or glucose tolerance following weight regain, these results illuminate new questions about the persistence and mechanisms by which exercise reduces tissue CD8+T cell exhaustion and the direct role of macrophages in modulating glucose tolerance with weight cycling.

immunology↗

bioRxiv2025

Interrupting T cell memory ameliorates exaggerated metabolic response to weight cycling

People frequently experience cycles of weight gain and loss. This weight cycling has been demonstrated, in humans and animal models, to increase cardiometabolic disease and disrupt glucose homeostasis. Obesity itself -- and to an even greater extent weight regain -- causes adipose tissue inflammation, resulting in metabolic dysfunction. Studies show that even after weight loss, increased numbers of lipid associated macrophages and memory T cells persist in adipose tissue and become more inflammatory upon weight regain. These findings suggest that the immune system retains a "memory" of obesity, which may contribute to the elevated inflammation and metabolic dysfunction associated with weight cycling. Here, we show that blocking the CD70-CD27 axis, critical for formation of immunological memory, decreases the number of memory T cells and reduces T cell clonality within adipose tissue after weight loss and weight cycling. Furthermore, while mice with impaired ability to create obesogenic immune memory have similar metabolic responses as wildtype mice to stable obesity, they are protected from the worsened glucose tolerance associated with weight cycling. Our data are the first to target metabolic consequences of weight cycling through an immunomodulatory mechanism. Thus, we propose a new avenue of therapeutic intervention by which targeting memory T cells can be leveraged to minimize the adverse consequences of weight cycling. These findings are particularly timely given the increasing use of efficacious weight loss drugs, which will likely lead to more instances of human weight cycling.

physiology↗

bioRxiv2024

Trem2 deficiency attenuates breast cancer tumor growth in lean, but not obese or weight loss, mice and is associated with alterations of clonal T cell populations

AbstractObesity is an established risk factor for breast cancer development and worsened prognosis; however, the mechanisms for this association - and the potential benefits of weight loss - have not been fully explored. The adipose environment surrounding breast tumors, which is inflamed in obesity, has been implicated in tumor progression. An emerging therapeutic target for cancer is TREM2, a transmembrane receptor of the immunoglobulin superfamily that is expressed on macrophages in adipose tissue and tumors. We utilized genetic loss of function (Trem2+/+ and Trem2-/-) models and dietary (lean, obese, and weight loss) intervention approaches to examine impacts on postmenopausal breast cancer. Remarkably, Trem2 deficiency ameliorated tumor growth in lean, but not obese or weight loss mice. Single-cell RNA sequencing, in conjunction with VDJ sequencing of tumor and tumor-adjacent mammary adipose tissue (mATTum-adj) immune cells, revealed that tumors of lean Trem2-/- mice exhibited a shift in clonal CD8+ T cells from an exhausted to an effector memory state, accompanied with increased clonality of CD4+ Th1 cells, that was not observed in any other diet-genotype group. Notably, identical T cell clonotypes were identified in the tumor and mATTum-adj of the same mouse. Finally, an immune checkpoint study demonstrated that PD-1 therapy restricted tumor growth in lean and weight loss, but not obese mice. We conclude that weight history is relevant when considering potential efficacy of TREM2 inhibition in postmenopausal breast cancer. This work reveals immunological interactions between tumors and surrounding adipose tissue, highlighting significant differences under obese and weight loss conditions.

cancer biology↗

bioRxiv2023

Insulin at the Intersection of Thermoregulation and Glucose Homeostasis

Mammals are protected from changes in environmental temperature by altering energetic processes that modify heat production. Insulin is the dominant stimulus of glucose uptake and metabolism, which are fundamental for thermogenic processes. The purpose of this work was to determine the interaction of ambient temperature induced changes in energy expenditure (EE) on the insulin sensitivity of glucose fluxes. Short-term and adaptive responses to thermoneutral temperature (TN, [~]28{degrees}C) and room (laboratory) temperature (RT, [~]22{degrees}C) were studied in mice. This range of temperature does not cause detectable changes in circulating catecholamines or shivering and postabsorptive glucose homeostasis is maintained. We tested the hypothesis that a decrease in EE that occurs with TN causes insulin resistance and that this reduction in insulin action and EE is reversed upon short term (<12h) transition to RT. Insulin-stimulated glucose disposal (Rd) and tissue specific glucose uptake were assessed combining isotopic tracers with hyperinsulinemic-euglycemic clamps. EE and insulin-stimulated Rd are both decreased ([~]50%) in TN-adapted vs RT-adapted mice. When RT-adapted mice are switched to TN, EE rapidly decreases and Rd is reduced by [~]50%. TN-adapted mice switched to RT exhibit a rapid increase in EE, but whole body insulin-stimulated Rd remains at the low rates of TN-adapted mice. In contrast, whole body glycolytic flux rose with EE. This higher EE occurs without increasing glucose uptake from the blood, but rather by diverting glucose from glucose storage to glycolysis. In addition to adaptations in insulin action, insulin-independent glucose uptake in brown fat is exquisitely sensitive to thermoregulation. These results show that insulin action adjusts to non-stressful changes in ambient temperature to contribute to the support of body temperature homeostasis without compromising glucose homeostasis. HighlightsO_LIEnergy expenditure and insulin-mediated glucose fluxes are reduced in thermoneutral (TN)-adapted mice versus room laboratory temperature (RT)-adapted mice. C_LIO_LIReduced insulin sensitivity manifests in TN mice regardless of whether they are TN-adapted or short-term transitioned from RT-adapted to TN. C_LIO_LITN-adapted mice are resistant to the RT-induced increase in whole-body insulin sensitivity even though metabolic rate is increased. C_LIO_LITN-adapted mice switched to RT meets increased thermogenic needs, not by increasing glucose uptake, but by partitioning a greater fraction of glucose from glycogen storage to glycolysis. C_LIO_LIBrown fat glucose uptake sensitively increases with RT and decreases with TN by an insulin-independent mechanism. C_LI

physiology↗

bioRxiv2022

PD-1 is induced on tumor-associated macrophages in obesity to directly restrain anti-tumor immunity

Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can also promote improved survival for some cancers3-5 and enhance responses to some immune checkpoint blockade therapies6-8. The role of the immune system in the obesity-cancer connection and how obesity influences immunotherapy, however, remain unclear. While PD-1 expression by macrophages has been described9-12, we found that obesity selectively induced PD-1 on macrophages and that PD-1 directly impaired macrophage function. Single cell RNA sequencing of murine colorectal carcinoma tumors showed obesity remodeled myeloid and T cell populations, with fewer clonally expanded effector T cells and increased abundance of PD-1+ tumor-associated macrophages (TAM). Cytokines and molecules associated with obesity, including IL-6, leptin, and insulin, and the unsaturated fatty acid palmitate, induced PD-1 expression on macrophages in a glycolysis-dependent manner. PD-1+ TAMs had increased mitochondrial respiration and expression of genes regulating oxidative phosphorylation, lipid uptake and cell cycle while PD-1- TAMs showed greater signatures of phagocytosis and antigen presentation to T cells. These patterns were directly regulated by PD-1, as recombinant PD-L1 reduced macrophage glycolysis and phagocytic capacity, and this was reversed with blocking PD-1 antibody. Conversely, PD-1-deficient Pdcd1-/- TAMs had high rates of glycolysis, phagocytosis, and expression of MHC-II. Myeloid-specific PD-1 deficiency correlated with slower tumor growth, enhanced TAM antigen presentation capability, and increased CD8 T cell activation together with reduced markers of exhaustion. These findings show metabolic signaling in obesity induces PD-1-mediated suppression of TAM function and reveal a unique macrophage-specific mechanism to modulate immune tumor surveillance and checkpoint blockade. This may contribute to increased cancer risk yet improved response to PD-1 blockade in TAM-enriched tumors and obesity.

immunology↗

bioRxiv2022

Weight cycling induces innate immune memory in adipose tissue macrophages

Weight loss improves obesity-associated diabetes risk. However, most individuals regain weight, which worsens the risk of developing diabetes and cardiovascular disease. We previously reported that male mice retain obesity-associated immunological changes even after weight loss, suggesting that immune cells may remember the state of obesity. Therefore, we hypothesized that cycles of weight gain and loss, otherwise known as weight cycling, can induce innate memory in adipose macrophages. We first treated bone marrow derived macrophages in a culture model of innate immune memory. Priming the cells with palmitic acid or adipose tissue conditioned media increased maximal glycolysis, oxidative phosphorylation, and increased LPS-induced TNF and IL-6 production. While weight loss improved glucose tolerance, adipose macrophages retained elevated LPS-induced cytokine production. In a model of weight cycling, adipose macrophages had elevated metabolism and secreted higher levels of basal TNF. Together, these data suggest that obesity and subsequent weight loss can prime adipose macrophages for enhanced inflammation upon weight regain. This innate immune memory response may contribute to worsened glucose tolerance following weight cycling.

immunology↗

bioRxiv2022

Trem2 deficiency does not worsen metabolic function in diet-induced obese mice

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.

physiology↗

bioRxiv2021

Multiomics reveals persistence of obesity-associated immune cell phenotypes in adipose tissue during weight loss and subsequent weight regain.

Most individuals do not maintain weight loss, and weight regain increases cardio-metabolic risk beyond that of obesity. Adipose inflammation directly contributes to insulin resistance; however, immune-related changes that occur with weight loss and weight regain are not well understood. Single cell RNA-sequencing was completed with CITE-sequencing and biological replicates to profile changes in murine immune subpopulations following obesity, weight loss, and weight cycling. Weight loss normalized glucose tolerance, however, type 2 immune cells did not repopulate adipose following weight loss. Many inflammatory populations persisted with weight loss and increased further following weight regain. Obesity drove T cell exhaustion and broad increases in antigen presentation, lipid handing, and inflammation that persisted with weight loss and weight cycling. This work provides critical groundwork for understanding the immunological causes of weight cycling-accelerated metabolic disease. Thus, we have created an open-access interactive portal for our processed data to improve accessibility for the research community.

immunology↗