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Energy expenditure through physical activity and dieting promotes weight loss. However, sustaining a healthy weight can be challenging and often a pattern known as weight cycling emerges. We evaluated the inflammatory status of mice undergoing weight cycling. Male C57BL/6 mice were randomized into four groups (n=10/group): low fat diet (LFD) for 32 weeks (LFD), high fat diet (HFD) for 32 weeks (HFD), LFD for 28 weeks then changed to HFD for 4 weeks (LFD->H), HFD for 21 weeks then changed to LFD for 7 weeks and then changed to HFD for 4 weeks (HFD->L->H). LFD->H and HFD->L->H mice did not significantly differ in body weight, body fat weight, or body fat percentage, but were significantly higher than LFD mice while remaining lower than HFD mice (pL->H mice had smaller adipocytes of the epididymal fat pad compared to HFD and LFD->H mice which both had larger adipocytes (pL->H mice compared to LFD and LFD->H mice. This was consistent with more M1-type macrophages (pL->H mice compared to LFD->H. Liver histopathological and protein analysis revealed HFD->L->H mice had greater NASH and NAS (p

Low-grade, chronic inflammation is thought to play a role in obesity-associated metabolic dysfunction. In obesity, macrophages account for approximately 50% of adipose tissue cells and can secrete a variety of proinflammatory cytokines. In this study, we sought to deplete macrophages in order to decrease macrophage-mediated inflammation and rescue metabolic dysfunction. Following 16 weeks of high-fat diet (HFD) (40% of total kcal from fat) or AIN-76A control diet consumption (n=30), male C57BL/6J mice within each diet cohort were assigned to either a clodronate (CLD)-liposome or PBS-liposome-treatment (n=15/group). Mice received 200 μl (1mg) i.p. injections of CLD or PBS-encapsulated liposomes (control group) twice weekly for 4 weeks to deplete macrophages. Metabolic function was assessed via the HOMA-IR, glucose and insulin tolerance tests, and serum free fatty acids. Adipose tissue, liver, and blood were analyzed for macrophage infiltration, inflammatory mediators and circulating cell populations. HFD-fed mice exhibited an obese phenotype compared to the control diet; however, macrophage depletion was unable to rescue metabolic dysfunction. Interestingly, macrophage-depleted mice had >35% increase in circulating neutrophils and adipose tissue Ly6G content. The increase in neutrophils, likely a compensation for the depletion of macrophages, was linked to an increase in the proinflammatory cytokines, IL-6 and IL1β, in the adipose tissue. Additionally, the decrease in macrophages resulted in iron-deficient anemia. Our study suggests that depleting macrophages in an obese setting is not an effective therapy for rescuing metabolic dysfunction and may increase the risk for anemia and adipose tissue inflammation.

Macrophages are recognized as major players in the connection between inflammation and cancer; they represent up to 50% of the tumor mass and produce a wide array of inflammatory mediators with pro-tumoral functions. Emerging evidence links gut microbiota to the development of colorectal cancer and host-derived immune and inflammatory responses are important driving forces that can shape microbial community composition. We used a macrophage depletion technique to examine the role of macrophages on colon tumorigenesis and gut microbiota. To induce colorectal cancer, male C57BL/6 mice (n=32) received a single injection of AOM followed by three cycles of DSS supplemented water at concentrations of 2%, 1%, 1% at weeks 1, 4, and 7, respectively. Prior to the final DSS cycle (week 7) and twice weekly until sacrifice, mice (n=16/group) received 200ul i.p. of clodronate (CL2MDP) or PBS encapsulated liposomes to deplete macrophages. Mice were sacrificed at 12 weeks following the initial AOM injection and colon tissue was analyzed for tumor burden, macrophage markers, and inflammatory mediators. Stool samples were collected and DNA was isolated and subsequently sequenced for 16S rRNA. Macrophage depletion decreased tumor number by ~35% and specifically large (≥1mm) tumors by ~35% (p

Macrophages have recently emerged as major players in the connection between inflammation and cancer; they represent up to 50% of the tumor mass and produce a wide array of inflammatory mediators with pro-tumoral functions. We used a macrophage depletion technique to examine the role of macrophages in colon cancer. To induce colon cancer, male C57BL/6 mice (n=20) received a single injection of AOM followed by three cycles of DSS supplemented water at concentrations of 2%, 1%, 1% at weeks 1, 4, and 7, respectively. Prior to the final DSS administration (week 7) and twice weekly thereafter for a duration of 5 weeks, mice (n=10/group) were administered 200μl of clodronate (CL2MDP) or PBS encapsulated liposomes via an intra-peritoneal route to deplete macrophages. Body weight, body composition, and symptom severity score were evaluated throughout the macrophage depletion period. Mice were sacrificed at 12 weeks following the initiation of colon cancer and colon tissue was analyzed for tumor burden, macrophage markers, and inflammatory mediators. There were no differences in body weight, body composition, or symptom severity score between the groups. Macrophage depletion decreased tumor number by ~25% and specifically medium tumor number by 50% (p