Metabolic Receptology in the Schwartz Group
The aim of the Schwartz Group is to understand the structural and functional basis for how signaling metabolites and their specific GPCR sensors control endocrine, metabolic and immune functions as the basis for developing novel means to prevent and treat obesity, diabetes and cancer.
Key metabolites generated from dietary nutrients, gut microbiota and intermediary metabolism function as extracellular messengers that are recognized by and signal through specific GPCRs in a similar manner as hormones and neurotransmitters. The metabolite GPCRs are particularly highly expressed and regulated in endocrine and metabolic cells – in particular adipocytes – as well as immune cells. The overarching hypothesis of the Schwartz Group is that metabolites such as succinate, lactate, ketones and acetate function as acute, auto- and paracrine signals of fuel availability and metabolic stress which are vital for enforcing metabolic homeostasis. However, these protective GPCR-mediated mechanisms can turn into damaging, disease-promoting inflammatory mechanism if the metabolite signaling becomes chronic or systemic and they are responsible for e.g. the survival and growth of cancer cells through metabolic reprogramming and immune evasion.
The group has a strong background in molecular pharmacology and structure-based drug discovery – in close collaboration with Thomas Frimurer – and a major strength is therefore the ability to combine powerful genetic models - often in collaboration with Zach Gerhart-Hines – with a large armamentarium of often unique proprietary pharmacological tools.
In this 2021 Cell Reports article we describe how physiological concentrations of succinate, a signal of metabolic stress, through SUCNR1 signaling upregulate the anti-inflammatory gene repertoire of M2 macrophages. This protective paracrine mechanism can become pro-inflammatory and cause NAFLD, diabetic retinopathy etc.
"Autocrine negative feedback regulation of lipolysis through sensing of NEFAs by FFAR4/GPR120 in WAT"
In this 2020 Molecular Metabolism paper we identify FFAR4 sensing of NEFAs as being responsible for a classical autocrine inhibitory feed-back loop controlling lipolysis in adipocytes and its potential co-action with multiple other GPCR-driven metabolite sensing autocrine mechanisms.
"L-Cell Differentiation Is Induced by Bile Acids Through GPBAR1 and Paracrine GLP-1 and Serotonin Signaling"
In this 2020 Diabetes paper we describe how the number and secretory capacity of L-cells can be increased to mimic effects of bariatric surgery by nutrient-derived metabolites and their GPCR sensors through a two-armed, serial paracrine mechanism involving GLP-1 stimulation of 5-HT secretion from neighboring enterochromaffin cells and 5-HT stimulation of HTR4 receptors on progenitor cells. This surprisingly identifies HTR4 as a target to control the secretory capacity of endogenous GLP-1 for treatment of diabetes and obesity.
"The lactate receptor GPR81 is responsible for metabolic reprogramming and immune evasion of cancer cells in solid tumors"
Innovation is a major force of the group. Together with Thomas Frimurer’s group we have developed first-in-class antagonists for GPR81 and – strongly supported by InnovationsFonden, NNF and BioInnnovation Institute (BII) – furthermore in the process of spinning out a biotech company, Warburg.
|Abiguime, Isis Paham
|Farshchi, Jasmin Kimya
|Goncalves Alves, Eliana Carolina
|Hjorth, Siv Annegrethe
|Visiting Associate Professor
|Iliyaz, Aslihan Shenol
|Johansen, Marianne Gregers
|Jørgensen, Kathrine Lundø
|Krusholt, Luna Li
|Lansbury, Elizabeth Laura
|Petersen, Jacob Emil
|Romeral Buzón, Alejandro
|Schwartz, Thue W.