The Role of Leptin Action in States of Obesity

Abstract

Over the last century, the United States has experienced a shift from underweight malnutrition maladies to obesity-associated complications. Today, over 70% of US adults are overweight and are at increased risk for various chronic diseases including diabetes, cardiovascular disease and cancer. The ubiquitous nature of obesity and its costs on the individual and societal level have elevated it to one of the most impactful diseases of the 21st century. The adipokine leptin is produced in proportion to adipose tissue and binds to its receptor (LepRb) in the CNS to provide a snapshot of energy stores, resulting in the regulation of energy balance. Due to leptin’s role in communicating fat stores and the hyperphagic obesity that results from its absence, leptin is clearly central to the homeostatic systems that regulate energy balance. And, while leptin replacement is an effective anti-obesity treatment in the few cases of obesity from leptin-deficiency, it fails to produce weight loss in diet-induced obese (DIO) individuals who express high levels of leptin (hyperleptinemia) commensurate with their elevated adipose content. Despite this, recent advances in genetic and sequencing technologies have allowed for a closer examination of DIO. We first examined the hypothalamic transcriptome of LepRb neurons and characterized DIO as a state of increased leptin signaling. Additional region-specific analyses confirm this understanding of DIO, and when coupled to immunohistochemical and phenotypic findings, broaden our understanding of the role DIO-hyperleptinemia plays in LepRb neurons and neighboring glial cells. These transcriptome findings additionally revealed STAT1 to be not only another LepRb-dependent signal, but to also significantly increase when STAT3 was ablated in neurons. This increase in Stat1, however, did not functionally compensate for the absence of STAT3. Moreover, we found STAT3 to be both necessary and sufficient in LepRb neurons for energy balance. However, while increased STAT3 activity does decrease weight in normoleptinemic mice (mimicking hyperleptinemia in lean animals) it does not produce weight loss in already hyperleptinemic DIO animals. Thus, the diminishing returns of additional STAT3/leptin action with increasing endogenous leptin levels were demonstrated transcriptionally, phenotypically and genetically. Our further investigation into the overlap between leptin and other metabolic hormones like calcitonin and amylin has broadened our understanding of leptin action and has identified potential molecular targets and locations for the already-proven synergistic amylin-leptin weight loss therapy. Together, these varied approaches underscore the complexity and importance of leptin action and paves a path for the discovery of novel anti-obesity therapies.