Obesity and the Brain

May 31- June 7, 2025

 

 

Director: Tamas Horvath

Yale University, New Haven, USA

 

Faculty:

Jeffrey Friedman, Rockefeller University, New York, USA

Amber AlhadeffUniversity of Pennsylvania, Philadelphia, USA

Matthias Tschöp, Technical University and Helmholtz Center, Munich, Germany

Marcelo Dietrich, Yale University, New Haven, USA

Cristina Garcia-Caceres, Helmholtz Center, Munich, Germany

Sabrina Diano, Columbia University, New York, USA

Roman Romanov, Medical University, Vienna, Austria

 

Significant progress has been made in recent years in understanding the role of the nervous system in obesity. Not only have several different neuronal pathways, neurotransmitters, and hormones been identified as major players in the regulation of feeding and body weight, but energy balance in mammals is also controlled by a complex network of interacting feedback mechanisms that involve peripheral organs in addition to higher brain centres.

This Advanced Course will cover the brain’s physiological and pathological regulation of energy metabolism and the impact of systemic metabolism on eating and other complex behaviours. It will also provide mechanistic insights regarding the action of a new generation of incretin-based anti-obesity drugs, which have been transformational in the treatment of obesity.

The Faculty represents diverse expertise in molecular, cellular, circuit, and behavioural approaches to contemporary questions regarding the role of the brain in systemic metabolism regulation and how the periphery affects complex brain functions via neuronal circuits and brain cells.

 

Matthias Tschöp

Overcoming Obesity: The Discovery of Multireceptor Drugs

The identification of the hunger hormone ghrelin revealed a fundamental metabolic control signal. Recognizing that one signal would not be sufficient to reverse obesity effectively, we started to combine several hormone action profiles into single hybrid molecules. Together with the chemists, we created dual and triple hormone-like peptides by strategically choosing specific amino acids from a pool of metabolically active gut hormones (e.g. GIP, GLP-1, Glucagon) as well as adding modifications to increase half-life, stability, and solubility. The result was a new class of therapeutics offering unprecedented levels of metabolic benefits and weight loss in obesity. We then validated the first types of these poly-agonists in rodent and primate models and led the very first clinical tests. Today, numerous pharmaceutical companies are advancing versions of these co-agonists through clinical trials. The FDA approved the first representative of this drug class, Tirzepatide.

 

Marcelo Dietrich

Developmental Origins of Obesity

These lectures will cover the development of feeding regulation in mammals, the neurocircuits involved, and how these circuits can be affected in ways that increase the predisposition to obesity. All mammals transition from breastfeeding to independent feeding during the lactation period—a critical phase for establishing metabolic control that influences the likelihood of many chronic conditions later in life. Dr. Dietrich will discuss the function of hypothalamic neurons in homeostatic control during this transition, emphasizing the unique properties of hypothalamic neurons in early life and adolescence. His presentations will suggest mechanisms by which early-life events shape homeostatic regulation across the individual’s lifespan.

 

Jeffrey Friedman

Obesity: Genetic bases, behavioural control and treatment

Obesity develops when food intake exceeds energy expenditure, leading to the deposition of excess calories as energy-dense triglycerides in adipose tissue. While obesity is often considered to be a lifestyle disease, we now know that food intake is controlled by neural circuits in the hypothalamus and brainstem that are regulated by interoceptive factors produced in adipose tissue and the intestine. Our understanding of the neural mechanisms regulating feeding was advanced by studies in mammals genetics, which enabled the identification of gene mutations leading to obesity in rodents and humans.

The following topics will be the focus of an in-depth review: (a) the genetic basis of obesity and the methods used to identify obesity genes revealing the components of a homeostatic system regulating weight; (b) general considerations on the control of behaviour; (c) our current understanding of the causes and treatment of obesity. This latter section will review the short- and long-term signals that maintain optimal levels of circulating nutrients and energy stores. These signals include leptin, a long-term signal from adipose tissue that maintains homeostatic control of adipose tissue mass, and GLP1 and other gut peptides that induce satiety to terminate a meal.

Leptin is the afferent signal in a negative feedback loop that maintains homeostatic control of adipose tissue mass. This endocrine system serves a critical evolutionary function by protecting individuals from the risks associated with being too thin (starvation) or too obese (predation). Leptin also links changes in nutrition to adaptive responses in other physiologic systems with effects on insulin sensitivity, fertility, immune function, and neuroendocrine function (among others). While most obese patients have high endogenous levels of leptin, indicating that they are leptin resistant, massively obese patients with leptin mutations show reduced food intake and robust weight loss with leptin treatment. Studies of leptin gene regulation also suggest that leptin may be an effective treatment for the subset of obese patients with low endogenous hormone levels. Other, more recent studies have revealed the pathogenesis of leptin resistance. The identification of leptin has thus provided a framework for studying the regulation of feeding behavior and understanding the pathogenesis of obesity.

The new anti-obesity therapeutics are ultra-stable versions of GLP1 and other intestinal hormones that target the short-term system to induce satiety bias effects on the brainstem and other sites. However, mutations in these genes do not alter weight. Thus, while identifying components of the short-term system has identified agents that have pharmacologic effects to induce weight loss, elucidating components of the long-term system has illuminated the pathogenesis of obesity. Moreover, elements of the short-term system interact with the long-term system, and preclinical and clinical studies have shown that these agents restore leptin signalling and synergize with it to induce even greater weight loss. These recent findings, based on new methods, will be reviewed together with a discussion of a conceptual framework for the control of feeding. 

 

Cristina Garcia-Caceres

Astrocytes and obesity

The lectures will focus on the role of astrocytes in the arcuate nucleus of the hypothalamus as a potential target for redirecting or resetting hunger circuits in overeating-induced obesity. Traditionally seen as merely supporting cells, astrocytes play a significant role in regulating hunger and food intake. By examining how these cells communicate with neurons and influence key pathways involved in appetite control, we aim to identify novel strategies for addressing obesity. Innovative approaches to modulate astrocyte function will help restore balance in hunger signalling to combat the effects of overeating on body weight.

 

Sabrina Diano

Brain response to circulating signals

The presentations will focus on the nutrient sensing that enables brain cells to sense and respond to changes in circulating signals in the control of food intake and energy and glucose metabolism, including mitochondrial mechanisms essential in regulating hypothalamic cell functions. By sensing and responding to changes in nutrient availability, brain cells are able, in turn, to alter behaviour and peripheral tissue functions to fine-tune systemic metabolism. This presentation will highlight these cellular biological processes in the hypothalamic regulation of energy and glucose homeostasis.

 

Roman Romanov

Hypothalamic cellular heterogeneity and eating behaviour

The main focus of these lectures is how the brain’s unprecedented cellular heterogeneity in the hypothalamus is achieved during development and converted into functional circuitry of metabolism regulation. Bridging experimental and computational approaches (single-cell transcriptomics analysis) has been instrumental in answering these questions. Also, multiple examples of research from the lab will be provided, including how cell-specific transcriptional programs are induced and act in specific cell types of the adult brain to process information and modulate functional outcomes, particularly eating.

 

Amber Alhadeff

Gut-brain signalling

The lectures will delve into the gut-brain signalling pathways that mediate food intake and how this is disrupted in obesity. We will also discuss current treatments for obesity, and in particular, the mechanisms for weight loss as well as side effects of GLP1-based medications. The presentations will highlight both foundational and recent work, and will also describe knowledge gaps where future neuroscience research can make major advancements in our understanding of the etiology and treatment of obesity.