Neuroendocrinology and Metabolism

The Sanz Lab is dedicated to understanding how the brain and mitochondria regulate fundamental aspects of reproduction and metabolism. Our central focus is on kisspeptin (Kiss1) neurons and their role in reproductive physiology. Kiss1 neurons are essential regulators of puberty onset and fertility, and specific subpopulations display remarkable sex-specific differences. We aim to determine how these neurons, particularly those located in the rostral periventricular area of the third ventricle (RP3V), contribute to male reproductive health.In parallel, we investigate how maternal nutrition shapes long-term metabolic health by disrupting hypothalamic circuits that control energy balance. We also study how mitochondrial activity regulates cellular energy production, with a focus on the phosphorylation of the Complex I subunit NDUFS4 at serine 173, a modification considered critical for proper protein maturation and optimal respiratory chain activity. By combining mouse genetics, viral circuit manipulation, molecular profiling, and behavioral analysis, we seek to reveal the cellular and molecular mechanisms that underlie reproduction, metabolism, and mitochondrial biology.

1. Define the sexual dimorphism and physiological role of Kiss1 neurons in the rostral periventricular area of the third ventricle (RP3V) in reproduction.
2. Define the neuroendocrine and metabolic pathways by which maternal nutrition programs the physiology of the offspring, with a focus on hypothalamic POMC and AgRP neurons.
3. Elucidate the role of mitochondrial activity in the brain, focusing on how phosphorylation of NDUFS4 at serine 173 regulates Complex I activity and impacts cellular energy metabolism.
4. Develop and apply advanced experimental approaches, including mouse genetics, viral vectors, and cell type-specific molecular profiling, to dissect the cellular and circuit-level mechanisms of neuroendocrine and metabolic regulation.
5. Translate basic discoveries into therapeutic strategies for conditions such as infertility, metabolic, and mitochondrial disorders.

• Kiss1 Neurons and Reproductive Function: Our core research line focuses on Kiss1 neurons in the rostral periventricular area of the third ventricle (RP3V). These neurons are abundant in females but scarce in males, a sexual dimorphism thought to underlie the female-specific ability to generate pre-ovulatory GnRH/LH surges. We use genetic models, molecular profiling, and behavioral assays to define the function of Kiss1RP3V neurons in male reproductive physiology and to explore how their activity integrates with broader neuroendocrine networks.
• Maternal Nutritional Programming of Hypothalamic Circuits: We investigate how maternal overnutrition during pregnancy and lactation disrupts the transcriptional profile of hypothalamic neurons (including POMC and AgRP populations) that regulate appetite, energy expenditure, and metabolic health. Our work combines cell-type specific molecular approaches to uncover how early-life nutritional environments predispose offspring to obesity and metabolic disorders.
• Mitochondrial Regulation of Cellular Energy Metabolism: We study how phosphorylation of the mitochondrial Complex I subunit NDUFS4 (Ser173) regulates protein maturation, respiratory chain function, and energy production. Using a novel Ndufs4 Ser173Ala mouse model that prevents this modification and allows cell type-specific rescue, we aim to uncover the physiological relevance of this regulatory mechanism.