Mount Sinai Center for Translational Medicine and Pharmacology

Obesity often results from a chronic positive energy balance, where calorie intake consistently exceeds energy expenditure. However, its development is also influenced by genetic, environmental, psychological, and metabolic factors. These influences contribute to the intricate nature of obesity, making it a challenging condition to address comprehensively.

Current Research in Hormonal Regulation and Metabolic Impact

Our program has collaboratively identified several pituitary hormones, including FSH, LH, and thyroid-stimulating hormone (TSH), which play crucial roles in regulating obesity and metabolism. FSH and LH are gonadotropins primarily responsible for reproductive functions. Notably, serum levels of both FSH and LH rise to variable levels after menopause. This period is marked by a significant increase in visceral adiposity, coinciding with disruptions in energy balance and a decline in physical activity.

Research Findings on FSH and LH

We discovered that blocking FSH can reduce visceral adiposity and improve energy homeostasis. In contrast, stimulating the LH receptor promotes leanness. These findings suggest that FSH and LH not only regulate reproductive functions but also have a significant impact on body fat distribution and metabolic health. The rise in FSH and LH levels post-menopause, and the associated increase in visceral fat, highlight the potential for these hormones to be targeted in obesity treatments.

The Role of TSH in Metabolism

Our research, in collaboration with the Neurohormone Program, has found that TSH plays a vital role in maintaining the integrity of the blood-brain barrier and in mediating communication among the hypothalamus, body fat, and the stomach. This crosstalk is essential to regulating feeding behavior, indicating that TSH has a broad influence on energy balance and metabolism beyond its traditional role in regulating thyroid function. By maintaining the blood-brain barrier and facilitating metabolic signals, TSH contributes to overall metabolic homeostasis.

Other Hormonal Influences

Several other hormones affect metabolism. Ghrelin, known as the "hunger hormone," stimulates appetite. In obesity, ghrelin levels do not decrease appropriately after eating, which can contribute to overeating. Insulin not only plays a role in glucose metabolism, but also influences fat storage. Hyperinsulinemia, often found in obesity, promotes lipogenesis and inhibits lipolysis, thus exacerbating weight gain. These hormonal disruptions further complicate the metabolic landscape in obesity. The lab of Ki A. Goosens, PhD, within the Neurohormone Program, is primarily focused on this aspect of obesity, particularly as it relates to stress.

Therapeutic Intervention

Addressing obesity requires interventions that can improve metabolic processes. In collaboration with the Therapeutic Antibody Program and the Biopharmaceutical and Nanomedicine Development CoRE, this group is actively testing several therapeutics in preclinical studies, including a humanized FSH-blocking antibody and small molecule agonists targeting LH and TSH receptors. These interventions have the potential to enhance metabolic health by promoting weight loss and reducing the comorbidities associated with obesity. By targeting specific hormonal pathways, these therapeutics aim to restore energy balance and reduce excess fat, ultimately offering an effective approach to manage obesity and related health issues.