Dr Pablo Enriori

BSc, M ClinEndocr, PhD (Univ Buenos Aires)

Research Fellow - Department of Physiology

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Background

Dr Pablo Enriori is a Research Fellow within the Metabolic Neuroscience  research group in the Department of Physiology. Enriori received his early training in Argentina. He earned a Biochemistry degree in 1988, a Master Degree in Clinical Endocrinology in 1996 and a Ph.D. in Endocrinology from the University of Buenos Aires in 2002. He moved to the United States to do postdoctoral work at the Oregon Health and Science University in the Cowley lab at Oregon National Primate Research Center in 2002. He joined Monash University in 2008.

Research Interests

“I am interested in gaining a better understanding of the physiological processes that balance energy intake and energy expenditure and how this balance is lost in obesity."

The focus of Dr Enriori's work is a group of specialized neurons in the arcuate nucleus of the hypothalamus (melanocortin neurons) which sense leptin levels and modify the body weight by decreasing food intake and increasing energy expenditure. Leptin is a hormone secreted by fat cells. It brings the information about the store of energy to the brain. Leptin can suppress food intake by affecting brain cells that control appetite. When humans and other animals become obese they lose the ability to regulate body weight in response to leptin.

 We recently discovered how obesity causes the breakdown of this brain system that regulates appetite. More specifically, we determined that leptin resistance prevented the arcuate nucleus from taking part in an important signaling function that regulates appetite and body weight. Our research provides new understanding of leptin resistance. We found that the melanocortin cells in obese mice behaved as if there was no leptin present, even though levels were 40-times higher than in normal animals. We also highlighted a key gene called SOCS-3 involved in the mechanism of leptin resistance.

Leptin resistance means that the body no longer responds to the hormone's weight suppressing effects. However, it is possible that leptin resistance is a selective resistance involving just some parts of the brain, and specifically associated with acute regulation of feeding. However, other neurons responsive to leptin could remain intact. In addition to its effects on appetite, Leptin also increases the activity of the sympathetic nervous system which stimulates energy expenditure in adipose tissue. In obesity, chronic activation of this leptin signalling may cause simpathoexcitation.

A primary research interest is to determine if high Leptin levels in the blood of obese mammals contribute to pathologically high blood pressure, increased heart rate, and decreased glucose metabolism, leading to diabetes/metabolic syndrome by activating the sympathetic nervous system. Another area of interest in his research is the fact that melanocortin neurons are not just involved in the control of energy balance. They can also regulate glucose homeostasis. In cases of Type 2 diabetes, the body's cells fail to appropriately regulate blood glucose levels. It is believed that this results from two simultaneous problems: the improper functioning of pancreatic beta cells and the impairment of insulin's actions on target tissues, including the liver, fat and muscles. Recently, our group in collaboration with researchers from Harvard Medical School, has identified a third abnormality that could play an important role in the development of obesity-induced Type 2 diabetes.

Some subpopulations of neurons in the brain become 'excited' by glucose. We discovered that some neurons that belong to the melanocortin system (POMC neurons) are able to sense increases in glucose and then initiate responses aimed at returning blood-glucose levels to normal. We demonstrated that POMC neurons of diabetic mice lose the capacity to sense changes in brain glucose levels, and we found that an increase in the activity of the mitochondrial uncoupling protein 2 is behind it. This is the first demonstration that glucose-sensing by neurons plays an important role in responding to rising blood glucose levels. This finding could potentially lead to novel treatments for Type 2 diabetes.

Publications

JM Scarlett, X Zhu, PJ Enriori, DD Bowe, AK Batra, PR Levasseur, WF Grant, MM Meguid, MA Cowley & DL Marks. (2008). Regulation of agouti-related protein messenger ribonucleic acid transcription and peptide secretion by acute and chronic inflammation. Endocrinology.  149(10):4837-45. Epub 26 Jun 2008.  PMID: 18583425 [PubMed - indexed for MEDLINE]

P Sinnayah, EE Jobst, JA Rathner, AD Caldera-Siu, LTonelli-Lemos, AJ Eusterbrock, PJ Enriori, EN Pothos, KL Grove & MA Cowley. (2008). Feeding induced by cannabinoids is mediated independently of the melanocortin system. PLoS One. May 21;3 (5):e2202.

LE Parton, CP Ye, R Coppari, PJ Enriori, B Choi, C-Y Zhang, C Xu, CR Vianna, N Balthasar, CE. Lee, JK. Elmquist, MA. Cowley, BB. Lowell. (2007). Glucose-sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature. 449: 228-32.

JM Scarlett, EE Jobst, PJ Enriori, DD Bowe, AK Batra, WF Grant, MA Cowley & DL Marks. (2007). Regulation of central melanocortin signaling by interleukin-1beta.Endocrinology. 148:4217-25.

PJ Enriori, AE Evans, P Sinnayah, EE Jobst, L Tonelli-Lemos, SK Billes, MM Glavas, BE Grayson, M Perello, EA Nillni, KL Grove, MA Cowley. (2007). Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell Metab. 5:181-194.

Y Guo, L Ma, PJ Enriori, J Koska, PW Franks, T Brookshire, MA Cowley, AD Salbe, A Delparigi, PA Tataranni. (2006). Physiological evidence for the involvement of peptide YY in the regulation of energy homeostasis in humans. Obesity (Silver Spring). 14(9):1562-70. PMID: 17030967 [PubMed - indexed for MEDLINE]

PJ Enriori, AE Evans, P Sinnayah, MA Cowley. (2006). Leptin resistance and obesity. Obesity (Silver Spring). 14 Suppl 5:254S-258S. Review. PMID: 17021377 [PubMed - indexed for MEDLINE]

T Reinehr, PJ Enriori, K Harz, MA Cowley, CL RothL. (2006).  Pancreatic polypeptide in obese children before and after weight loss. Int J Obes (Lond). 30(10):1476-81. Epub 2006 May 16. PMID: 16702998 [PubMed - indexed for MEDLINE]

EE Jobst, PJ Enriori, P Sinnayah, MA Cowley. (2006). Hypothalamic regulatory pathways and potential obesity treatment targets. Endocrine. 29(1):33-48. Review. PMID: 16622291 [PubMed - indexed for MEDLINE]

PJ Enriori, SM Vázquez, V Chiauzzi, C Pérez, CR Fischer, JR Gori, AE Etkin, E Charreau, RS Calandra, IA Lüthy. (2006). Breast cyst fluids increase the proliferation of breast cell lines in correlation with their hormone and growth factor concentration. Clin Endocrinol (Oxf). 64(1):20-8. PMID: 16402924 [PubMed - indexed for MEDLINE]

FH Koegler, PJ Enriori, SK Billes, DL Takahashi, MS Martin, RL Clark, AE Evans, KL Grove, JL Cameron & MA Cowley.  (2005).  PYY_(3-36) inhibits morning, but not evening, food intake and decreases body weight in rhesus macaques.  Diabetes, 54: 3198-204.

CL Roth, PJ Enriori, K Harz, J Woelfle, MA Cowley, T Reinehr. (2005). Peptide YY is a regulator of energy homeostasis in obese children before and after weight loss. J Clin Endocrinol Metab. 90(12):6386-91. Epub 2005 Oct 4. PMID: 16204364 [PubMed - indexed for MEDLINE]

EE Jobst, PJ Enriori, MA Cowley. (2004). The electrophysiology of feeding circuits. Trends Endocrinol Metab. 15(10):488-99. Review. PMID: 15541648 [PubMed - indexed for MEDLINE]

PJ Enriori, CR Fischer, JR Gori, AE Etkin, RS Calandra, IA Lüthy. (2003). Augmented serum levels of the IGF-I/IGF-binding protein-3 ratio in pre-menopausal patients with type I breast cysts. Eur J Endocrinol. 148(2):177-84. PMID: 12590636 [PubMed - indexed for MEDLINE]

PJ Enriori, CL Enriori. (2002). The pathogenesis of osteoporosis in older women and men: a review. J Steroid Biochem Mol Biol. 82(1):1-6. Review. No abstract available. PMID: 12429134 [PubMed - indexed for MEDLINE]

PJ Enriori, RJ Hirsig, CM Vico, AE Etkin, JC Negri, CL Enriori. (2000).  Effect of natural "micronized" progesterone on the chorionic gonadotropin concentrations in cyst fluids of women with gross cystic breast disease. J Steroid Biochem Mol Biol. 73(1-2):67-70. PMID: 10822026 [PubMed - indexed for MEDLINE]

CL Enriori, JE Novelli, Mdel C Cremona, RJ Hirsig, PJ Enriori. (1992). Biochemical study of cyst fluid in human breast cystic disease: a review. Breast Cancer Res Treat. 24(1):1-9. Review. PMID: 1463866 [PubMed - indexed for MEDLINE]

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