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Sadeesh Ramakrishnan, DVM, PhD
Assistant Professor of Medicine,
Division of Endocrinology and Metabolism,
University of Pittsburgh School of Medicine
Obesity is a key contributor to the growing epidemic of metabolic and cardiovascular diseases. According to the most recent health statistics from the World Health Organization (WHO), more than 13 percent of the global population and 40 percent of Americans are obese (defined as a body mass index of ≥ 30).1 The prevalence and severity of obesity are not only rising in adults but also in children and adolescents. As of 2013, the American Medical Association (AMA) officially designated obesity as a chronic disease.2 In addition, obesity often is associated with many other chronic and progressive diseases, including diabetes and fatty liver disease. Clearly, there is an urgent need to improve the understanding and treatment of obesity and related metabolic disorders.
The intestine (gut) was previously recognized solely for its role in nutrient absorption, but it is now recognized as playing a much more complex role in systemic metabolic and immune function. The intestine is the largest endocrine organ of the body, secreting more than 30 gut hormones.3-5 These gut hormones have peripheral as well as central nervous system (CNS) effects in regulating energy and metabolic homeostasis. For example, glucagon-like peptides, such as glucagon-like peptide 1 (GLP1), are secreted by the intestinal endocrine (enteroendocrine) cells. In peripheral tissues, GLP1 augments pancreatic insulin secretion, improves insulin sensitivity, and promotes energy expenditure. In the CNS, GLP1 activates the satiety center, thereby reducing food intake. These effects are the foundation for the well-known clinical therapies such as GLP1 agonists (which mimic the effects GLP1) and dipeptidyl peptidase-4 (DPP-4) inhibitors (which delay the breakdown of GLP1). Likewise, the beneficial effects of bariatric surgery are believed to be, at least in part, due to alterations in gut hormones. Despite their critical importance, the mechanisms that regulate the intestinal secretion of gut hormones remain poorly understood.
Just as oxygen is required for whole-body survival, so is oxygen required for cell survival. Oxygen is required for cells to efficiently generate energy for essential cellular functions. Not surprisingly then, cells have developed very sensitive mechanisms to detect and respond to even minor fluctuations in oxygen tension at the cellular or tissue level, even when whole-body oxygen in the lungs and blood are normal. This oxygen sensing is mediated by hypoxia signaling via hypoxia-inducible factors (HIFs) (i.e., HIF-1, HIF-2). When oxygen levels are low or decreasing, these highly conserved proteins help cells survive by switching their metabolism to conserve available oxygen for vital cellular functions. HIFs conserve available oxygen by regulating the expression of numerous genes involved in cell stress, survival, proliferation, death, and metabolism. HIFs also influence the immune response. Thus, “hypoxia signaling” is critically important for metabolic homeostasis.6-8
Hypoxia signaling has been implicated in the pathogenesis of obesity and its metabolic complication. Obesity is well known to promote the accumulation of “toxic” fats in multiple tissues, including the liver and intestines. Regarding the former, the laboratory of Sadeesh Ramakrishnan, DVM, PhD, from the Division of Endocrinology and Metabolism at the University of Pittsburgh School of Medicine, has demonstrated an important role for HIFs, specifically HIF-2α, in hepatic glucose homeostasis and insulin action.9,10 Regarding the latter, Dr. Ramakrishnan’s collaborative group has demonstrated that HIF-2α signaling in the intestines drives the obesity-associated increase in “toxic” fats and leads to fatty liver (hepatic steatosis). Conversely, inhibition of intestinal HIF-2α signaling abolishes this obesity-associated increase in “toxic” fats and protects against fatty liver. This data suggests that inhibition of intestinal hypoxia signaling may have therapeutic potential in preventing or treating obesity-associated metabolic diseases.11 Preclinical testing in mice indicates that a HIF-2-specific pharmaco-logical inhibitor protects against diet-induced weight gain, hepatic steatosis, and inflammation. These data suggest that inhibition of HIF-2 can be an effective therapeutic target for metabolic disease and supports the need for future studies in humans.
In the intestine, HIFs, and in particularly HIF-2, are expressed in the epithelial and endocrine cells. In the epithelial cells, HIF-2 regulates iron absorption and homeostasis.12 Pharmacological stabilizers of HIF-2 (i.e., Roxadustat or FG-4592) are currently in phase III clinical trials for the treatment of anemia of chronic disease.13
Despite this ongoing research, the role of HIFs in enteroendocrine cells remains unknown. The Ramakrishnan lab has unveiled novel evidence linking hypoxia signaling to gut hormones and vice versa, specifically implicating HIF-2α in gut hormone secretion from enteroendocrine cells. Ongoing studies are using cell type-specific preclinical models to manipulate HIF-2α expression in enteroendocrine cells in order to systematically dissect their cellular and physiological role in regulating gut hormone secretion. Another area of intense investigation is whether HIF-2α may mediate some of the metabolic effects of gut microbiota via its effects on GLP1 and other gut hormones. These studies may not only reveal novel therapeutic potential of targeting HIFs but may impact our understanding of existing therapies that target GLP1 or other gut hormones.
In summary, the gut is an important endocrine organ that plays a critical role in normal metabolism and disease. Cellular hypoxia signaling and hypoxia-inducible factors are becoming increasingly recognized as important metabolic sensors and mediators in the gut. Researchers at the University of Pittsburgh are working to understand the metabolic effects and therapeutic potential of hypoxia signaling in the gut. Understanding these pathways may improve the prevention and treatment of metabolic diseases, including, but not limited to, obesity.
1 World Health Organization: Obesity. https://www.who.int/topics/obesity/en/.
2 Pollack A. AMA Recognizes Obesity as a Disease. [Internet]. 2013 [cited 2014 Nov 20]. Available from: http://www.nytimes.com/
3 Sun EWL, Martin AM, Young RL, Keating DJ. The Regulation of Peripheral Metabolism by Gut-derived Hormones. Front Endocrinol (Lausanne). 2019 Jan 4; 9: 754.
4 Melvin A, le Roux CW, Docherty NG. The Gut as an Endocrine Organ: Role in Regulation of Food Intake and Body Weight. Curr Atheroscler Rep. 2016 Aug; 18(8): 49.
5 Reinehr T, Roth CL. The Gut Sensor as Regulator of Body Weight. Endocrine. 2015 May; 49(1): 35-50.
6 Lee JW, Ko J, Ju C, Eltzschig HK. Hypoxia Signaling in Human Diseases and Therapeutic Targets. Exp Mol Med. 2019 Jun 20; 51(6): 68.
7 Gonzalez FJ, Xie C, Jiang C. The Role of Hypoxia-inducible Factors in Metabolic Diseases. Nat Rev Endocrinol. 2018 Dec; 15(1): 21-32.
8 Ramakrishnan SK, Shah YM. Role of Intestinal HIF-2α in Health and Disease. Annu Rev Physiol. 2016; 78: 301-325.
9 Ramakrishnan SK, Zhang H, Takahashi S, Centofanti B, Periyasamy S, Weisz K, Chen Z, Uhler MD, Rui L, Gonzalez FJ, Shah YM. HIF2α Is an Essential Molecular Brake for Postprandial Hepatic Glucagon Response Independent of Insulin Signaling. Cell Metab. 2016 Mar 8; 23(3): 505-516.
10 Ramakrishnan SK, Shah YM. A Central Role for Hypoxia-inducible Factor (HIF)-2α in Hepatic Glucose Homeostasis. Nutr Healthy Aging. 2017
Dec 7; 4(3): 207-216.
11 Xie C, Yagai T, Luo Y, Liang X, Chen T, Wang Q, Sun D, Zhao J, Ramakrishnan SK, Sun L, Jiang C, Xue X, Tian Y, Krausz KW, Patterson AD, Shah YM, Wu Y, Jiang C, Gonzalez FJ. Activation of Intestinal Hypoxia-inducible Factor 2α During Obesity Contributes to Hepatic Steatosis. Nat Med. 2017 Nov; 23(11): 1298-1308.
12 Sanghani NS, Haase VH. Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis. 2019 Jul; 26(4): 253-266.
13 Mastrogiannaki M, Matak P, Peyssonnaux C. The Gut in Iron Homeostasis: Role of HIF-2 Under Normal and Pathological Conditions. Blood. 2013 Aug 8; 122(6): 885-92.