Partial leptin deficiency confers resistance to diet-induced obesity in mice

Authors: ZHAO, SHANGANG - University Of Texas Southwestern Medical Center; LI, NA - University Of Texas Southwestern Medical Center; ZHU, YI - Children'S Nutrition Research Center (CNRC); STRAUB, LEON - University Of Texas Southwestern Medical Center; ZHANG, ZHUZHEN - University Of Texas Southwestern Medical Center; WANG, MAY-YUN - University Of Texas Southwestern Medical Center; ZHU, QINGZHANG - University Of Texas Southwestern Medical Center; KUSMINSKI, CHRISTINE - University Of Texas Southwestern Medical Center; ELMQUIST, JOEL - University Of Texas Southwestern Medical Center; SCHERER, PHILIPP - University Of Texas Southwestern Medical Center

Submitted to: Molecular Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/6/2020
Publication Date: 4/11/2020
Citation: Zhao, S., Li, N., Zhu, Y., Straub, L., Zhang, Z., Wang, M., Zhu, Q., Kusminski, C.M., Elmquist, J.K., Scherer, P.E. 2020. Partial leptin deficiency confers resistance to diet-induced obesity in mice. Molecular Metabolism. 37:100995. https://doi.org/10.1016/j.molmet.2020.100995.
DOI: https://doi.org/10.1016/j.molmet.2020.100995

Interpretive Summary: The overconsumption of calorically dense foods coupled to a sedentary lifestyle dramatically increases the risk for the development of obesity. Leptin is a master regulator of appetite and obesity which is secreted from adipose tissue. This paper demonstrates less leptin protects mice from diet-induced obesity and metabolic dysregulation, suggesting reducing leptin may be an approach to combat obesity.

Technical Abstract: 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. 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. 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. 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.