The neurobiology of anorexia nervosa : focus on short-chain fatty acids, GDF15, and hypothalamic regulation of food intake

<p dir="ltr">Anorexia nervosa (AN) is an eating disorder characterized by persistent food restriction accompanied by markedly low body weight in relation to age, sex, and developmental trajectory. We currently lack evidence-based pharmacological treatment for AN, likely because we do not have sufficient knowledge about the etiology of the disorder. One perplexing phenomenon in AN is the aberrant response to starvation and emaciation. While most individuals quickly regain lost weight, individuals with AN remain in an underweight state, not rarely for years.</p><p dir="ltr">The main purpose of this thesis is to explore why AN patients stay in a negative energy balance. To this end, we used a multidimensional approach to study changes in the gut, blood, and brain of AN patients during and after the onset of the disorder. This includes clinical biomarker studies using plasma collected from patients, cellular modeling based on patient-derived induced pluripotent stem cells (iPSC), as well as high-resolution spatial omics applied to a rodent model of anorexia.</p><p dir="ltr">In Study I, we measured the plasma concentration of short-chain fatty acids (SCFAs) in females with AN, recovered from AN (AN-REC), and healthy individuals. We showed reduced butyric, isobutyric, and isovaleric acids in AN and AN-REC compared to the controls.</p><p dir="ltr">In Study II, we analyzed the level of growth and differentiation factor 15 (GDF15) in the plasma of AN, AN-REC, and healthy female controls. There was no significant difference in GDF15 levels among the three groups, but a subgroup of study participants, mostly AN, had increased plasma GDF15 levels, combined with increased fibroblast growth factor 21, indicative of mitochondrial dysfunction. Using a large AN case-control cohort, we found that mitochondrial polygenic risk scores were significantly associated with the risk of AN.</p><p dir="ltr">In Study III, we differentiated fibroblast-derived induced pluripotent stem cells from AN patients and healthy controls into microglia, hypothalamic neurons, and cortical neurons. We demonstrated that microglia from AN patients had an altered ability to engulf synaptosomes extracted from hypothalamic neurons compared with healthy controls, both before and after treatment with glucagon- like peptide-1, whereas no such difference was observed when the same microglia were used to phagocytose cortical synaptosomes.</p><p dir="ltr">In Study IV, we profiled selected hypothalamic regions and, selectively, the agouti-related peptide (AgRP) expressing neurons of the anorectic anx/anx mouse using spatial transcriptomics. We reported changed expressions of genes related to immune response, synapses, and myelin in several of the anx/anx hypothalamic regions, and the AgRP neurons of the anx/anx mouse exhibited changed expression of genes regulating energy homeostasis and mitochondrial metabolism.</p><p dir="ltr">The work presented here highlights our efforts to understand the biological changes that occur from the gut to the blood to the brain in patients with AN. I believe our research will contribute to the discovery of therapeutic targets and, in the long term, to the development of effective medications for AN, the most lethal psychiatric disorder.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Jingjing Xu</b>, Rikard Landberg, Catharina Lavebratt, Cynthia M Bulik, Mikael Landen & Ida AK Nilsson</p><p dir="ltr">Plasma Concentrations of Short-Chain Fatty Acids in Active and Recovered Anorexia Nervosa <br>Nutrients, 2022, 14(24), 5247<br><a href="https://doi.org/10.3390/nu14245247" rel="noreferrer" target="_blank">https://doi.org/10.3390/nu14245247</a></p><p><br></p><p dir="ltr">II. <b>Jingjing Xu</b>, Ruyue Zhang, Vincent Millischer, Miranda Stiernborg, Claire E Tume, Sara Mehdinia, Peter Barker, Zeynep Yilmaz, Vanessa F Gonçalves, Catharina Lavebratt, Mikael Landen, Stephen O'Rahilly, Cynthia M Bulik & Ida AK Nilsson</p><p dir="ltr">Elevated plasma GDF15 combined with FGF21 suggests mitochondrial dysfunction in a subgroup of anorexia nervosa patients<br>Translational psychiatry, 2025, 15(1), 215</p><p dir="ltr"><a href="https://doi.org/10.1038/s41398-025-03425-0" rel="noreferrer" target="_blank">https://doi.org/10.1038/s41398-025-03425-0</a></p><p dir="ltr">III. <b>Jingjing Xu</b>, Emmy Erskine, Barbara Eramo, Tianxu Feng, Karin Zimmer, Chiara Camoglio, Funda Orhan, Lars Selander, Tomas Hokfelt, Martin Schalling, Samudyta, Carl Sellgren & Ida AK Nilsson</p><p dir="ltr">Microglia pruning of hypothalamic synapses is reduced in anorexia nervosa, 2025 [Manuscript]</p><p dir="ltr">IV. <b>Jingjing Xu</b>, Emmy Erskine, Barbara Eramo, Chiara Camoglio, Lars Selander, Tomas Hökfelt & Ida AK Nilsson</p><p dir="ltr">Spatial transcriptomic profiling of the hypothalamus of the anorectic anx/anx mice, 2025 [Manuscript]</p>