Leptin, Obesity, and Leptin Resistance: Where Are We 25 Years Later?
Leptin, a hormone that is capable of effectively reducing food intake and body weight, was initially considered for use in the treatment of obesity. However, obese subjects have since been found to have high levels of circulating leptin and to be insensitive to the exogenous administration of leptin...
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| Published in | Nutrients Vol. 11; no. 11; p. 2704 |
|---|---|
| Main Authors | , , , |
| Format | Journal Article |
| Language | English |
| Published |
Switzerland
MDPI AG
08.11.2019
MDPI |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Leptin, a hormone that is capable of effectively reducing food intake and body weight, was initially considered for use in the treatment of obesity. However, obese subjects have since been found to have high levels of circulating leptin and to be insensitive to the exogenous administration of leptin. The inability of leptin to exert its anorexigenic effects in obese individuals, and therefore, the lack of clinical utility of leptin in obesity, is defined as leptin resistance. This phenomenon has not yet been adequately characterized. Elucidation of the molecular mechanisms underlying leptin resistance is of vital importance for the application of leptin as an effective treatment for obesity. Leptin must cross the blood–brain barrier (BBB) to reach the hypothalamus and exert its anorexigenic functions. The mechanisms involved in leptin transportation across the blood–brain barrier continue to be unclear, thereby preventing the clinical application of leptin in the treatment of obesity. In recent years, new strategies have been developed to recover the response to leptin in obesity. We have summarized these strategies in this review. |
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| AbstractList | Leptin, a hormone that is capable of effectively reducing food intake and body weight, was initially considered for use in the treatment of obesity. However, obese subjects have since been found to have high levels of circulating leptin and to be insensitive to the exogenous administration of leptin. The inability of leptin to exert its anorexigenic effects in obese individuals, and therefore, the lack of clinical utility of leptin in obesity, is defined as leptin resistance. This phenomenon has not yet been adequately characterized. Elucidation of the molecular mechanisms underlying leptin resistance is of vital importance for the application of leptin as an effective treatment for obesity. Leptin must cross the blood–brain barrier (BBB) to reach the hypothalamus and exert its anorexigenic functions. The mechanisms involved in leptin transportation across the blood–brain barrier continue to be unclear, thereby preventing the clinical application of leptin in the treatment of obesity. In recent years, new strategies have been developed to recover the response to leptin in obesity. We have summarized these strategies in this review. Leptin, a hormone that is capable of effectively reducing food intake and body weight, was initially considered for use in the treatment of obesity. However, obese subjects have since been found to have high levels of circulating leptin and to be insensitive to the exogenous administration of leptin. The inability of leptin to exert its anorexigenic effects in obese individuals, and therefore, the lack of clinical utility of leptin in obesity, is defined as leptin resistance. This phenomenon has not yet been adequately characterized. Elucidation of the molecular mechanisms underlying leptin resistance is of vital importance for the application of leptin as an effective treatment for obesity. Leptin must cross the blood-brain barrier (BBB) to reach the hypothalamus and exert its anorexigenic functions. The mechanisms involved in leptin transportation across the blood-brain barrier continue to be unclear, thereby preventing the clinical application of leptin in the treatment of obesity. In recent years, new strategies have been developed to recover the response to leptin in obesity. We have summarized these strategies in this review.Leptin, a hormone that is capable of effectively reducing food intake and body weight, was initially considered for use in the treatment of obesity. However, obese subjects have since been found to have high levels of circulating leptin and to be insensitive to the exogenous administration of leptin. The inability of leptin to exert its anorexigenic effects in obese individuals, and therefore, the lack of clinical utility of leptin in obesity, is defined as leptin resistance. This phenomenon has not yet been adequately characterized. Elucidation of the molecular mechanisms underlying leptin resistance is of vital importance for the application of leptin as an effective treatment for obesity. Leptin must cross the blood-brain barrier (BBB) to reach the hypothalamus and exert its anorexigenic functions. The mechanisms involved in leptin transportation across the blood-brain barrier continue to be unclear, thereby preventing the clinical application of leptin in the treatment of obesity. In recent years, new strategies have been developed to recover the response to leptin in obesity. We have summarized these strategies in this review. Several studies have shown that obese mice are sensitive to intracerebro-ventricular (ICV), but not subcutaneous or intraperitoneal (IP), or the administration of leptin [15,16], indicating that the lack of leptin activity is due to 35% decrease in BBB permeability [10]. [...]the cerebrospinal fluid/serum leptin ratio in obese humans is 4–5 times lower [17,18]. The entry of leptin into the brain is partially saturable [20], which indicates the involvement of a protein transporter. [...]leptin transport by tanycytes in the MHB requires the presence of the leptin receptor (OBR) [21] as well as the short isoforms of the receptor (OBRa and OBRc) [22,23,24,25,26], which are highly expressed in the BBB. [...]therapies that mobilize the OBR from intracellular pools and allow for increased OBR on the cell surface might be useful in achieving greater sensitivity to leptin in obesity. Other compounds such as fluvoxamine, a serotonin reuptake inhibitor, and flurbiprofen, a molecule with anti-inflammatory capacity, are able to reduce ER stress and leptin resistance along with causing weight loss in murine models [90,91]. Because various neuropeptides can be delivered into the central nervous system through an intranasal administration route, intranasal leptin might prove an effective treatment approach for obesity. |
| Author | Carreira, Marcos C. Casanueva, Felipe F. Crujeiras, Ana B. Izquierdo, Andrea G. |
| AuthorAffiliation | 2 CIBER de Fisiopatologia de la Obesidad y Nutricion (CIBERobn), Instituto Salud Carlos III, 28029 Madrid, Spain 4 Molecular Endocrinolgy, Universidad de Santiago de Compostela (USC), 15706 Santiago de Compostela, Spain 1 Laboratory of Epigenomics in Endocrinology and Nutrition, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), 15706 Santiago de Compostela, Spain; andrea.gonzalez.izquierdo@hotmail.com (A.G.I.); anabelencrujeiras@hotmail.com (A.B.C.) 3 Laboratory of Molecular Endocrinology, Instituto de Investigacion Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), 15706 Santiago de Compostela, Spain |
| AuthorAffiliation_xml | – name: 2 CIBER de Fisiopatologia de la Obesidad y Nutricion (CIBERobn), Instituto Salud Carlos III, 28029 Madrid, Spain – name: 3 Laboratory of Molecular Endocrinology, Instituto de Investigacion Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), 15706 Santiago de Compostela, Spain – name: 1 Laboratory of Epigenomics in Endocrinology and Nutrition, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), 15706 Santiago de Compostela, Spain; andrea.gonzalez.izquierdo@hotmail.com (A.G.I.); anabelencrujeiras@hotmail.com (A.B.C.) – name: 4 Molecular Endocrinolgy, Universidad de Santiago de Compostela (USC), 15706 Santiago de Compostela, Spain |
| Author_xml | – sequence: 1 givenname: Andrea G. orcidid: 0000-0002-0846-8834 surname: Izquierdo fullname: Izquierdo, Andrea G. – sequence: 2 givenname: Ana B. orcidid: 0000-0003-4392-0301 surname: Crujeiras fullname: Crujeiras, Ana B. – sequence: 3 givenname: Felipe F. orcidid: 0000-0002-9052-8161 surname: Casanueva fullname: Casanueva, Felipe F. – sequence: 4 givenname: Marcos C. surname: Carreira fullname: Carreira, Marcos C. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31717265$$D View this record in MEDLINE/PubMed |
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| Title | Leptin, Obesity, and Leptin Resistance: Where Are We 25 Years Later? |
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