Primary: Biological Sciences, Secondary: CMMG
Research interest(s)/area of expertise
- Obesity and Diabetes
- Nutrient-sensing hypothalamic circuits
- Neurobiology of aging
- Early postnatal environment
The prevalence of obesity in adults and children has increased globally at an alarming rate. The Sadagurski Lab employs a multi-disciplinary approach to manipulate brain neurocircuits and nutrient sensing pathways using cutting-edge molecular, genetics, and metabolic assessments in rodents to characterize developmental origins of obesity and metabolic syndrome. Through her research, Dr. Sadagurski hopes to identify new therapies to prevent and/or treat obesity and type 2 diabetes.
Early-life nutrition and inflammation
The major focus of our research is to investigate the molecular basis of the relationship between early life nutrient environment and increased risk of obesity, inflammation and diabetes. The hypothalamic appetite signaling pathways are crucial in these processes and are altered following alterations in the maternal nutritional environment in fetal and postnatal offspring. Our new data suggests that obesity and obesity-induced hypothalamic inflammation might be predisposed by maternal diet. To understand mechanisms by which early postnatal environment influences the development of obesity in adulthood, we are studying the molecular links between early-life dietary nutrition and hypothalamic inflammatory signals.
Our project investigates the influence of the early-life nutrition on hypothalamic glia cells (astrocytes and microglia), in modulating to a lasting proinflammatory profile that contributes to the development of obesity. We utilize genetically modified mice models as well as in vitro systems to study metabolic and epigenetic alterations, to identify early-life markers in hypothalamic nutrient inflammatory pathways that may contribute to the development of obesity and type 2 diabetes.
Human studies: Human blood samples are used to establish relationship between the expression pattern of inflammatory markers to the nutritional status of both mother and baby.
Aging and hypothalamic inflammation
Our data shows that aging leads to hypothalamic inflammation, but does so more slowly in mice whose lifespan has been extended by mutations that affect GH/IGF-1 signals. Specifically, early-life exposure to GH by injection, or to early-life nutrient restriction, also modulate both lifespan and the pace of hypothalamic inflammation. Our new data demonstrates that three anti-aging drugs (ACA; acarbose, 17αE2; 17-α-estradiol and NDGA; nordihydroguaiaretic acid) induce changes in hypothalamic inflammatory processes that are sexually dimorphic in a pattern that parallels the effects of these agents on mouse longevity. We are currently engaged in mechanistic testing for studying differences between male and female mice for control of aging and neuro-inflammation in old drug-treated mice. We focus on identification of molecular mechanisms that are relevant to sexual dimorphisms in glial cells to explore the potential for targeting neuro-inflammatory signals in extend longevity.
Nutrient-sensing hypothalamic pathways and metabolic dysfunction
Growth hormone (GH) signaling plays a major part in the regulation of glucose metabolism. In the brain, GH secretion contributes to rescue glucose levels in response to hypoglycemia. One intriguing populations of neurons known to have glucose lowering effects are leptin receptor (LepRb) expressing neurons. These neurons regulate metabolism (including glycemic control) and endocrine function. Our new data shows that these nutrient-sensing, LepRb neurons are crucial for the metabolic effects of hypothalamic GH signaling. Our lab is currently developing novel genetic mice models that will elucidate the involvement of specific hypothalamic neuronal circuits in the context of metabolic disorders and obesity. These studies will provide a critical insight into the brain systems that link GH/GHR axis with glucose control.
- 2000-2006, Ph.D. Tel Aviv University, Israel
- 2006-2012, Postdoc, Harvard Medical School, HHMI (advisor: Morris White)
- 2012-2015, Assistant Research Scientist, University of Michigan (Richard Miller lab)
- 2015-2016, Assistant Research Professor,University of Michigan
Awards and grants
2001 Young investigator award, International Symposium on Insulin Receptor and Insulin Action award, Geneva, Switzerland
2001 Dean's Award, Tel-Aviv University, Israel
2002 Travel Grant award from 38th Annual Meeting of the EASD, Hungary
2003 Minerva Short-Term Student Research Grant, (DKFZ), Germany
2004 Dean's Award, Tel-Aviv University, Israel
2003-2005 NIH-TAU Graduate Excellence Partnership Program, NIDDK, NIH
2010 Young investigator award, American Diabetes Association
2010 Postdoctoral travel award, American Diabetes Association, Orlando, FL
2013 Travel award, 2013 Alliance for Healthy Aging Symposium, Groningen, Netherlands
2018 Junior Faculty Development Award American Diabetes Association
Ongoing Research support
Wayne State University startup funding
JDF, American Diabetes Association 1-18-JDF-063 (1/1/2018-1/1/2022)
Cady G and Sadagurski M. Targeting neuroinflammation - a potential for anti-aging interventions. Aging 2017, 9, 1951-1952
Cady G, Landeryou T, Kopchick JJ, List EO, Berryman DE, Elias C, Myers MG, Miller RA, Sadagurski M. Growth hormone receptor (GHR) in nutrient-sensing neurons regulates hepatic glucose production. Molecular Metabolism 2017.
Sadagurski M*, Cady G, Miller RA (Corresponding author). Anti-Aging Drugs Reduce Hypothalamic Inflammation in a Sex-Specific Manner. Aging Cell 2017.
Kuznetsova A, Yu Y, Hollister-Lock J, Opare-Addo L, Rozzo A, Sadagurski M, Norquay L, Reed JE, El Khattabi I, Bonner-Weir S, Weir GC, Sharma A, White MF. Tricyclic compounds that increase IRS2 in human Islets and promote beta-cell growth and function in mice. J Clin Invest. Insight. 2016 Mar 17
Sadagurski M*, Landeryou T, Cady G, Kopchick JJ, List EO, Berryman DE, Bartke A, and Miller RA (Corresponding author). Growth Hormone Modulates Hypothalamic Inflammation in Long-Lived Pituitary Dwarf Mice. Aging Cell 2015 Aug 12
Sadagurski M*, Landeryou T, Cady G, Bartke A, Bernal-Mizrachi E and Miller RA. Transient early food restriction leads to hypothalamic changes in the long-lived crowded litter (CL) mice. (Corresponding author) Physiological Reports 2015 Apr 3(4)
Sadagurski M*, Landeryou T, Blandino-Rosano M, Cady G, Elghazi L, Meister D, See L, Bartke A, Bernal-Mizrachi E and Miller RA. Long-lived crowded litter (CL) mice exhibit lasting effects on insulin sensitivity and energy homeostasis. (Corresponding author) Am J Physiol Endocrinol Metab. 2014 Apr 15.
Sadagurski M, Dong X, Myers MG and White MF. Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis. Molecular Metabolism. 2013 Oct 23;3(1):55-63.
Sadagurski M and White MF. Integrating metabolism and longevity through insulin and IGF1 signaling. Endocrinol Metab Clin North Am. 2013 Mar;42(1): 127-148.
Sadagurski M, Leshan RL, Patterson C, Rozzo A, Dong X, Skorupski J, Depinho R Myers MG, and White MF. IRS2 signaling in LepR-b neurons suppresses FoxO1 to control energy balance independently of leptin action. Cell Metabolism. 2012 May 2;15 (5):703-712.
Sadagurski M, Cheng Z, Rozzo A, Palazzolo I, Dong X, Krainc D and White MF. IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease. J Clin Invest. 2011 Oct 3;121(10):4070-81.
Sadagurski M, Norquay L, Farhang-Fallah J, Copps K, and White MF. Human IL6 enhances leptin action in mice. Diabetologia. 2010 Mar;53(3):525-35.
Sadagurski M, Nofech-Mozes S, Spravchikov N, Weingarten G, Teruachi Y, White MF, Kadowaki T and Wertheimer E. Insulin receptor substrate 1 (IRS-1) plays a unique role in normal epidermal physiology. J Cell Physiol. 2007 Nov;213(2):519-27.
Sadagurski M, Yakar S, Weingarten G, Holzenberger M, Rhodes CJ, Breitkreutz D, LeRoith D and Wertheimer E. IGF-1 receptor signaling regulates skin development and inhibits skin keratinocytes differentiation. Mol Cell Biol. 2006 Apr;26(7):2675-87.
Sadagurski M, Weingarten G, Rhodes CJ, White MF and Wertheimer E. Insulin receptor substrate 2 (IRS-2) plays diverse cell-specific roles in the regulation of glucose transport. J Biol Chem. 2005 Apr 15; 280(15):14536-44.
- 4012 Comparative Physiology (2018 fall semester)
2017 Graduate students’ seminar, WSU (2 credits, winter semester)
2017 4012 Comparative Physiology (3 credits, fall semester)
2018 5067 Selective topics on Central regulation of obesity (3 credits, winter semester)