# A leptin-responsive lateral hypothalamus to ventrolateral periaqueductal gray circuit for palatable food overconsumption > **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2022 · $437,300 ## Abstract PROJECT SUMMARY/ABSTRACT Obesity is a global public health crisis, and its prevalence continued to increase dramatically during the last three decades. Although numerous factors influence on body weight, excessive consumption of palatable foods (e.g., high-fat diet, HFD) is a major risk factor leading to obesity. Notably, most of the individuals who achieved a successful diet with withdrawal from such foods show high rates of relapse to HFD overconsumption. Given that this process is highly associated with the increased preference for palatable foods, understanding neural circuit mechanisms leading to HFD overconsumption after abstinence is arguably the core issue in therapeutic strategies for the long-term treatment of obesity. However, neither the specific neural circuit pathway nor the molecular mechanisms underlying this process are well understood. Leptin, an adipose tissue-derived hormone, exerts its anorexic effects by acting on its receptors in the hypothalamus. Activation of long leptin receptor (LepR) stimulates multiple signal transduction pathways to suppress food intake and weight gain. While a decrease in hypothalamic tissue sensitivity to leptin is characterized by a disturbance in the ability of LepR to activate downstream effectors or impairment in LepR expression, we do not understand critical issues concerning primary brain circuit that develops leptin insensitivity which can subserve relapse to HFD overconsumption. Thus, in this proposal we aim to propose an interdisciplinary approach to understand the circuit-specific role of leptin sensitivity in driving HFD overconsumption following abstinence from such foods. We will primarily focus on the leptin-responsive circuit that connects the lateral hypothalamus (LH) to the ventrolateral periaqueductal gray (vlPAG) and functionally probe its neural adaptation after HFD exposure. The central objective of this proposal is to determine the neural dysfunction of LepR-expressing LH (LepR LH) neurons projecting to the vlPAG using the intermittent access schedule of HFD to better understand the neural mechanisms underlying HFD overconsumption when the food becomes more salient. To achieve our objective, we will first characterize in vivo activity of target-specific LepR LH neurons during HFD consumption at different food stages. We will examine whether the vlPAG-projecting LepR LH neurons are engaged in post-abstinence HFD overconsumption (Aim 1). Secondly, using molecular profiling methods, we will examine how HFD abstinence induces circuit- specific neural adaptation in the LepR signaling associated with HFD overconsumption (Aim 2). Third, we will determine how LepR knockdown-induced leptin insensitivity in the LepR LH neurons regulates HFD consumption and body weight with a circuit-specific manner (Aim 3). The significance of this study is substantial because it represents the first steps towards understanding how leptin-responsive LH-vlPAG circuitry controls HFD consumption that is ex... ## Key facts - **NIH application ID:** 10422524 - **Project number:** 1R01DK132566-01 - **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV - **Principal Investigator:** Sora Shin - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $437,300 - **Award type:** 1 - **Project period:** 2022-04-07 → 2027-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10422524 ## Citation > US National Institutes of Health, RePORTER application 10422524, A leptin-responsive lateral hypothalamus to ventrolateral periaqueductal gray circuit for palatable food overconsumption (1R01DK132566-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10422524. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*