Makowski Lab stairsMy expertise lies in immunometabolism, notably macrophage biology and inflammation, metabolomics, mouse models of obesity, and nutrient sensitive signaling pathways. The research focus of my laboratory is to understand metabolic reprogramming of immune cells to limit the pathogenesis of complex diseases such as obesity, diabetes, and cancer. My ultimate aim is to find relevant metabolically sensitive pathways in model systems, observe parallels in human populations, and identify targets to reprogram immune cells to restore tissue homeostasis to limit disease. To date, I have received multiple grants including a NIH Pathway to Independence K99/R00 award to investigate macrophage mitochondria’s role in metabolism and inflammation in obesity. I am currently PI on an NIH R21 Provocative Question Grant and completed a Mary Kay Foundation grant to study obesity and breast cancer risk. I was also PI on an American Heart Association grant to study substrate metabolism in macrophage biology in atherosclerosis. Finally, I was co-PI on a BCERP U01 from NIEHS/NCI and co-I on two Department of Defense grants to examine cancer risk and progression integrating obesity, metabolism, and oncogenic pathways. Recent grants have funded investigation of metabolic reprogramming of macrophages in obesity-induced breast cancer.

Contribution to Science

# Denotes students and postdoctoral fellows mentored by Makowski.

1) Established the role of obesity and weight loss in basal-like breast cancer using translational multi-disciplinary approaches.

Macrophage-cancer-image2Historical background: Obesity leads to many types of cancer, but mechanisms are unclear. The work conducted in my lab or in collaboration with other research groups has reported upon effects of obesity, diet exposure, weight loss, and pharmacologic interventions with a unique approach to tumorigenesis. Central findings: 1) We have utilized a pre-clinical model that faithfully resembles human phenotypes to further identify risk factors and test potential therapeutic pathways. Using a unique murine model that resembles human basal-like breast cancer, we demonstrated that high fat diet-induced obesity drove aggressive tumor behavior – e.g., early tumor onset and tumor growth – potentially through growth factors and inflammatory cytokines regulated by diet. 2) We identified the HGF/cMet pathway as an obesity-driven oncogenic target, which had not been previously identified in any cancer type as obesity sensitive. We published the first evidence for obesity-induced HGF and activation of its receptor cMet in the etiology of basal-like breast cancer, which could be reversed with weight loss. Obesity-driven activation of several kinases in the normal mammary gland were detected that could be reversed by weight loss. We also demonstrated that obesity drives ovarian cancer. We provided evidence of the importance of stromal-epithelial interactions in cancer promotion. Influence/application of findings: These findings are seminal in the understanding that the obese microenvironment shapes cancer risk and progression. Based on these findings, I was awarded two grants including a highly competitive NCI Provocative Question R21 to address the role of weight loss in reducing BBC through reversal of obesity-associated factors. We further established lack of knowledge of breast cancer subtypes and risk through community interactions and focus groups and created outreach and education materials including a website/app through the UNC Breast Cancer ( and the Environment Research Program (BCERP,

#Qin Y, #Sundaram S, #Essaid L, Miller SM, Darr DB, Galanko JA, Montgomery SA, Major B, Johnson GL, Troester MA, Makowski L. Remodeling the Microenvironment by Weight Loss Restrained High Fat Diet-Induced Basal-like Breast Tumor Progression. 16:26 Cancer Cell International. 1 April 2016

#Cozzo AJ*,#Sundaram S*, #Ottavia Zattra O,#Qin Y, Freemerman AJ,#Essaid L,Dar DB, Montgomery SA, McNaughton KK, Ezzell JA, Galanko JA,Troester MA, Makowski L. cMET inhibitor crizotinib impairs angiogenesis and reduces tumor burden in the C3(1)-Tag model of basal-like breast cancer. Springer Plus Breast Cancer Collection Springerplus. 2016 Mar 19;5:348. PMID: 27057482 PMCID: PMC4799044 *denotes co-first authorship

#Sundaram S, #Le TL, #Essaid L, Freemerman AJ, #Huang MJ, Galanko JA, McNaughton KK, Bendt KM, Darr DB, Troester MA, Makowski L. Weight loss prevents obesity-associated basal-like breast cancer progression: Role of hepatocyte growth factor. Frontiers in Oncology 2014 Jul 8;4:175. PMID: 25072025

#Sundaram S, Freemerman AJ, Galanko JA, McNaughton KK, Bendt KM, Darr DB, Troester MA, Makowski, L. Obesity-mediated regulation of HGF/c-Met is associated with reduced basal-like breast cancer latency in parous mice. PLoS One. 2014 Oct 29;9(10):e111394. 2014. PMID: 25354395

#Sundaram S, Freemerman AJ, McNaughton KK, Galanko JA, Bendt KM, Darr DB, Perou CM, Troester MA, Makowski, L. Role of HGF in obesity-associated tumorigenesis: C3(1)-Tag mice as a model for human basal-like breast cancer. Breast Cancer Res Treat. 2013 Dec;142(3):489-503. doi: 10.1007/s10549-013-2741-5. Epub 2013 Nov 12. PMID:24218051. PMC3904507.

Roque DR, Makowski L, Chen T-H, Rashid N, Hayes, DN, Bae-Jump V. Association between differential gene expression and body mass index among endometrial cancers from The Cancer Genome Atlas Project. Gynecologic Oncology. Submitted.

2) Demonstrated that metabolic reprogramming of substrate metabolism, glycolysis, and lipid trafficking direct macrophage biology in obesity and atherosclerosis. 

23-b-and-f-RGB-A9-GLUT1-overexp-1024x780Historical background: MΦs are known to infiltrate adipose tissue at the onset of weight gain; however, many questions remain about how MΦ phenotypes are regulated within the adipose or vessel microenvironment with regard to lipid metabolism and along the classical (M1) versus alternative (M2) polarization spectrum, as well as mixed M1/M2. We hypothesized that starving cells of certain substrates by deleting transporters would alter immune function- in this way we could metabolically reprogram macrophages to alter the course of disease. Central findings: Our central findings demonstrated that the availability of fuel substrate is indeed a modifier of macrophage plasticity through metabolic reprogramming. We employed innovative techniques including metabolomics, cellular bioenergetics analyses, and radiotracer studies to prove that pro-inflammatory cytokine production is influenced by simply enhancing glucose metabolism in vitro, with in vivo supportive evidence. We reported that fatty acid transport protein FATP1 regulates macrophage lipid metabolism and glucose tolerance (Johnson, in press). Based upon the same premise that controlling macrophage substrate metabolism will alter the immune response, we showed that GLUT1 expression drove glucose uptake, reactive oxygen species generation, and inflammation in macrophages (Freemerman J Biol Chem 2014- which currently has 57 citations since 2014). We discovered defects in macrophage infiltration and pro-inflammatory activation in the absence of macrophage GLUT1 when mice were made obese (Freemerman, manuscript in preparation). We next turned to another macrophage-dependent disease: atherosclerosis. In our project funded by the AHA, we found that both GLUT1 and FATP1 altered atherogenesis and plaque stability. Furthermore, GLUT1, we discovered, is central for the phagocytic capacity of macrophages and may contribute to necrosis in an atherosclerotic lesion (Zhao, manuscript in preparation). FATP1 regulates the size and severity of atherosclerotic lesions (Zhao, manuscript in preparation). Influence/application of findings: These studies clarified metabolic mechanisms leading to inflammation, atherosclerosis, and glucose intolerance.

#Johnson AR*, #Qin YY*, #Cozzo A, Freemerman AJ, #Huang MJ, #Zhao L, #Sampey BP, #Milner JJ, Beck MA, Edin ML, Zeldin D, Galanko JA, Lee DP, Fueger PT, Damania B, Bivins B, Stahl A, Wu Y, Mohlke K, Makowski L. Macrophage Fatty Acid Transporter 1 (FATP1) Drives Alternative Macrophage Polarization and Limits Obesity-Induced Inflammation. *denotes co-first authorship. Molecular Metabolism, IN PRESS.

Torres AM, Makowski L, Wellen KE. Metabolism fine-tunes macrophage activation. Elife. 2016 Feb 19;5. pii: e14354. doi: 10.7554/eLife.14354. PMID: 26894957.

Freemerman AJ, #Johnson AR, #Sacks GN, #Milner JJ, Kirk EL, Troester MA, Macintyre AN, Goraksha-Hicks P, Rathmell JC, Makowski L. Metabolic reprogramming of macrophages: Glucose Transporter (GLUT1)- mediated glucose metabolism drives a pro- inflammatory phenotype. J Biol Chem. 2014 Feb 3. PMID: 24492615. PMC3953299.

3) Established the inflammatory potential of varied diets, exposures, and specific metabolites. 

Sampey Makowski Cover Obesity 2011Historical background: Inflammation is linked to obesity, diabetes and some cancers, but the specific mechanisms remain unclear. We hypothesized that inflammatory and metabolic biomarkers of risk associated with inflammation, insulin resistance, and diabetes could identify pathways to target in control of obesity-induced pathology. Central findings: We defined metabolic biomarkers of obesity-induced inflammation and beta-oxidative metabolism in adipose tissue (Sampey Obesity 2011 – which as 195 citations). We presented novel findings on macrophage infiltration into BAT tissue with a dramatic lack of crown like structures detected but significant macrophage staining around vessels where fat droplets accumulated. Subsequently, using high throughput metabolomic analysis, we identified novel lipid metabolites as biomarkers of insulin resistance and adipose inflammation. We then demonstrated in vitro that a specific metabolite induced the production of classical pro-inflammatory cytokines associated with diabetes using bone marrow derived macrophages. A current analysis of gene expression associated with the CAF diet showed oxidative stress. Influence/application of findings: These novel findings have important implications for the study design of diet-induced obesity animal studies as well as implications for human examinations of diet’s effects on inflammation in liver, white and brown fat. This model provides a unique platform to further study the biochemical, genomic and physiological mechanisms of obesity and obesity-related disease states that are pandemic in Western civilization today. The Obesity manuscript was featured on the cover of the journal Obesity. The PLOS One study was featured on National Public Radio.

#Qin Y, #Hamilton J, Bird MA, Chen MM, Ramirez L, Zahs A, Kovacs EJ, Makowski L. Adipose inflammation and macrophage infiltration after binge ethanol and burn injury. Alcoholism-Clinical and Experimental Research,2014 Jan;38(1):204-13. doi: 10.1111/acer.12210. Epub 2013 Aug 1. (p. 1-10).

#Johnson AR, Wilkerson MD, #Sampey BP, Troester MA, Hayes DN, Makowski L. Cafeteria Diet Induced Obesity Results in Increased Oxidative Damage in White Adipose.  BBRC. 2016 Mar 28. PMID: 27033600

#Sampey BP, Freemerman AJ, #Zhang J, Kuan PF, Galanko JA, O’Connell TM, Ilkayeva OR, Muehlbauer MJ, Stevens RD, Newgard CB, Brauer HA, Troester MA, Makowski L. Metabolomic Profiling Reveals Mitochondrial-Derived Lipid Biomarkers that Drive Obesity-Associated Inflammation. PLoS One. 2012;7(6):e38812. Epub 2012 Jun 12. PMID: 22701716. PMC3373493.

#Sampey BP, Vanhoose AM, Winfield H, Freemerman AJ, Muehlbauer M, Fueger PT, Newgard CB, and   Makowski L. Cafeteria-Diet is a Robust Model of Human Metabolic Syndrome with Liver and Adipose Inflammation: Comparison to High Fat Diet. Obesity (Silver Spring). Jun;19(6):1109-17. Epub 2011 Feb 17.PMID: 21331068. 2011. PMC3130193.

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