Partial leptin deficiency confers resistance to diet-induced obesity in mice
Objective: Hyperleptinemia per se is sufficient to promote leptin resistance in the obese state. Leptin sensitivity can be restored by reducing circulating leptin levels within a physiologically healthy range and is a viable antiobesity and antidiabetic strategy. However, a previous study suggests t...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-07-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877820300697 |
| _version_ | 1828722615639867392 |
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| author | Shangang Zhao Na Li Yi Zhu Leon Straub Zhuzhen Zhang May-Yun Wang Qingzhang Zhu Christine M. Kusminski Joel K. Elmquist Philipp E. Scherer |
| author_facet | Shangang Zhao Na Li Yi Zhu Leon Straub Zhuzhen Zhang May-Yun Wang Qingzhang Zhu Christine M. Kusminski Joel K. Elmquist Philipp E. Scherer |
| author_sort | Shangang Zhao |
| collection | DOAJ |
| description | Objective: Hyperleptinemia per se is sufficient to promote leptin resistance in the obese state. Leptin sensitivity can be restored by reducing circulating leptin levels within a physiologically healthy range and is a viable antiobesity and antidiabetic strategy. However, a previous study suggests that partial leptin deficiency favors diet-induced obesity and related metabolic disorders in mice, arguing that a lower leptin level may indeed promote diet-induced obesity and its associated metabolic disorders. Here, we aim to elucidate what the impact of partial leptin deficiency is on fat mass and insulin sensitivity. Methods: We used two different mouse models of partial leptin deficiency: an adipocyte-specific congenital heterozygous leptin knockout mouse line (LepHZ) and the well-established whole body heterozygous leptin knockout mouse (OBHZ). The metabolic studies of OBHZ and LepHZ mice were performed both on normal carbohydrate-rich chow diet and on a high-fat diet (HFD). Male and female mice were included in the study to account for sex-specific differences. Body weight, food intake, glucose tolerance, and insulin tolerance were tested. Histology of adipose tissue and liver tissue allowed insights into adipose tissue inflammation and hepatic triglyceride content. Immunohistochemistry was paired with RT-PCR analysis for expression levels of inflammatory markers. Results: Both OBHZ and LepHZ mice displayed reduced circulating leptin levels on the chow diet and HFD. On chow diet, male OBHZ and LepHZ mice showed elevated fat mass and body weight, while their glucose tolerance and insulin sensitivity remained unchanged. However, the inability in partially leptin-deficient mice to fully induce circulating leptin during the development of diet-induced obesity results in reduced food intake and leaner mice with lower body weight compared to their littermate controls. Importantly, a strong reduction of adipose tissue inflammation is observed along with improvements in insulin sensitivity and enhanced glucose tolerance. Additionally, partial leptin deficiency protects the mice from fatty liver and liver fibrosis. Chronically HFD-fed OBHZ and LepHZ mice remain more sensitive to exogenous leptin injection, as reflected by their reduced food intake upon an acute leptin treatment. Conclusion: In response to HFD feeding, the inability to upregulate leptin levels due to partial leptin deficiency protects mice from diet-induced obesity and metabolic dysregulation. Thus, in an obesogenic environment, maintaining lower leptin levels is highly beneficial for both obesity and diabetes management. Chronic leptin reduction represents a viable preventive strategy whose efficacy awaits clinical testing. |
| first_indexed | 2024-04-12T09:16:10Z |
| format | Article |
| id | doaj.art-76d4cc69627b42cf972695e63e028106 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-12T09:16:10Z |
| publishDate | 2020-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-76d4cc69627b42cf972695e63e0281062022-12-22T03:38:50ZengElsevierMolecular Metabolism2212-87782020-07-0137100995Partial leptin deficiency confers resistance to diet-induced obesity in miceShangang Zhao0Na Li1Yi Zhu2Leon Straub3Zhuzhen Zhang4May-Yun Wang5Qingzhang Zhu6Christine M. Kusminski7Joel K. Elmquist8Philipp E. Scherer9Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, 300052, ChinaTouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USADivision of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USATouchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Corresponding author.Objective: Hyperleptinemia per se is sufficient to promote leptin resistance in the obese state. Leptin sensitivity can be restored by reducing circulating leptin levels within a physiologically healthy range and is a viable antiobesity and antidiabetic strategy. However, a previous study suggests that partial leptin deficiency favors diet-induced obesity and related metabolic disorders in mice, arguing that a lower leptin level may indeed promote diet-induced obesity and its associated metabolic disorders. Here, we aim to elucidate what the impact of partial leptin deficiency is on fat mass and insulin sensitivity. Methods: We used two different mouse models of partial leptin deficiency: an adipocyte-specific congenital heterozygous leptin knockout mouse line (LepHZ) and the well-established whole body heterozygous leptin knockout mouse (OBHZ). The metabolic studies of OBHZ and LepHZ mice were performed both on normal carbohydrate-rich chow diet and on a high-fat diet (HFD). Male and female mice were included in the study to account for sex-specific differences. Body weight, food intake, glucose tolerance, and insulin tolerance were tested. Histology of adipose tissue and liver tissue allowed insights into adipose tissue inflammation and hepatic triglyceride content. Immunohistochemistry was paired with RT-PCR analysis for expression levels of inflammatory markers. Results: Both OBHZ and LepHZ mice displayed reduced circulating leptin levels on the chow diet and HFD. On chow diet, male OBHZ and LepHZ mice showed elevated fat mass and body weight, while their glucose tolerance and insulin sensitivity remained unchanged. However, the inability in partially leptin-deficient mice to fully induce circulating leptin during the development of diet-induced obesity results in reduced food intake and leaner mice with lower body weight compared to their littermate controls. Importantly, a strong reduction of adipose tissue inflammation is observed along with improvements in insulin sensitivity and enhanced glucose tolerance. Additionally, partial leptin deficiency protects the mice from fatty liver and liver fibrosis. Chronically HFD-fed OBHZ and LepHZ mice remain more sensitive to exogenous leptin injection, as reflected by their reduced food intake upon an acute leptin treatment. Conclusion: In response to HFD feeding, the inability to upregulate leptin levels due to partial leptin deficiency protects mice from diet-induced obesity and metabolic dysregulation. Thus, in an obesogenic environment, maintaining lower leptin levels is highly beneficial for both obesity and diabetes management. Chronic leptin reduction represents a viable preventive strategy whose efficacy awaits clinical testing.http://www.sciencedirect.com/science/article/pii/S2212877820300697LeptinPartial leptin deficiencyLeptin resistanceAdipose tissue inflammationFatty liverLiver fibrosis |
| spellingShingle | Shangang Zhao Na Li Yi Zhu Leon Straub Zhuzhen Zhang May-Yun Wang Qingzhang Zhu Christine M. Kusminski Joel K. Elmquist Philipp E. Scherer Partial leptin deficiency confers resistance to diet-induced obesity in mice Molecular Metabolism Leptin Partial leptin deficiency Leptin resistance Adipose tissue inflammation Fatty liver Liver fibrosis |
| title | Partial leptin deficiency confers resistance to diet-induced obesity in mice |
| title_full | Partial leptin deficiency confers resistance to diet-induced obesity in mice |
| title_fullStr | Partial leptin deficiency confers resistance to diet-induced obesity in mice |
| title_full_unstemmed | Partial leptin deficiency confers resistance to diet-induced obesity in mice |
| title_short | Partial leptin deficiency confers resistance to diet-induced obesity in mice |
| title_sort | partial leptin deficiency confers resistance to diet induced obesity in mice |
| topic | Leptin Partial leptin deficiency Leptin resistance Adipose tissue inflammation Fatty liver Liver fibrosis |
| url | http://www.sciencedirect.com/science/article/pii/S2212877820300697 |
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