How Overeating Rewires Our Brains – The Neuroscience of Obesity, Weight Gain, & Weight Loss

Some of the earliest changes in obesity are invisible – and they start in the brain.

Many of the brain changes that accompany obesity bear a concerning resemblance to those that occur in brain injury. In this episode, we discuss how overnutrition can lead to inflammation and neuron dysfunction in specific parts of the brain that control appetite and energy regulation. We review the neuroscience of appetite regulation, energy expenditure, and body fat regulation. Topics include hypothalamic dysfunction of body fat regulation, leptin resistance, neuro-inflammation, and physical changes in the hypothalamus involving microglia (the immune cells of the brain). We also review what is known about avoiding and reversing these changes.

References

Montague, C. T., I. S. Farooqi, J. P. Whitehead, M. A. Soos, H. Rau, N. J. Wareham, C. P. Sewter, et al. 1997. “Congenital Leptin Deficiency Is Associated with Severe Early-Onset Obesity in Humans.” Nature 387 (6636): 903–8.

Farooqi, I. S., S. A. Jebb, G. Langmack, E. Lawrence, C. H. Cheetham, A. M. Prentice, I. A. Hughes, M. A. McCamish, and S. O’Rahilly. 1999. “Effects of Recombinant Leptin Therapy in a Child with Congenital Leptin Deficiency.” The New England Journal of Medicine 341 (12): 879–84.

Beck, Harvey G. 1920. “HYPOPHYSEAL DISORDERS WITH SPECIAL REFERENCE TO FROELICH’S SYNDROME (DYSTROPHIA ADIPOSOGENITALIS).” Endocrinology 4 (2): 185–98.

Fröhlich, Alfred. 1901. Ein Fall von Tumor der Hypophysis cerebri ohne Akromegalie. Fröhlich, Alfred. 1901. Ein Fall von Tumor der Hypophysis cerebri ohne Akromegalie.

Babinski, J. n.d. “Tumeur Du Corps Pituitaire sans Acromégalie et Avec Arrêt de Développement Des Organes Génitaux.” Revista de Neurologia.

Brobeck, J. R., J. Tepperman, and C. N. Long. 1943. “Experimental Hypothalamic Hyperphagia in the Albino Rat.” The Yale Journal of Biology and Medicine 15 (6): 831–53.

Locke, Adam E., The LifeLines Cohort Study, Bratati Kahali, Sonja I. Berndt, Anne E. Justice, Tune H. Pers, Felix R. Day, et al. 2015. “Genetic Studies of Body Mass Index Yield New Insights for Obesity Biology.” Nature 518 (7538): 197–206.

Brooks, C. M., R. A. Lockwood, and M. L. Wiggins. 1946. “A Study of the Effect of Hypothalamic Lesions on the Eating Habits of the Albino Rat.” The American Journal of Physiology 147 (4): 735–41.

Stenger, Janet, Thomas Fournier, and Catherine Bielajew. 1991. “The Effects of Chronic Ventromedial Hypothalamic Stimulation on Weight Gain in Rats.” Physiology & Behavior. https://doi.org/10.1016/0031-9384(91)90584-b.

Anand, B. K., and J. R. Brobeck. 1951. “Localization of a ‘Feeding Center’ in the Hypothalamus of the Rat.” Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine 77 (2): 323–24.

Lee, Darrin J., Gavin J. B. Elias, and Andres M. Lozano. 2018. “Neuromodulation for the Treatment of Eating Disorders and Obesity.” Therapeutic Advances in Psychopharmacology 8 (2): 73–92.

Ingalls, A. M., M. M. Dickie, and G. D. Snell. 1950. “Obese, a New Mutation in the House Mouse.” The Journal of Heredity 41 (12): 317–18.

Li, Min-Dian. 2011. “Leptin and beyond: An Odyssey to the Central Control of Body Weight.” The Yale Journal of Biology and Medicine 84 (1): 1–7.

Huvenne, Hélène, Béatrice Dubern, Karine Clément, and Christine Poitou. 2016. “Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016.” Obesity Facts 9 (3): 158–73.

Simonds, Stephanie E., Jack T. Pryor, Eric Ravussin, Frank L. Greenway, Ralph Dileone, Andrew M. Allen, Jaspreet Bassi, et al. 2014. “Leptin Mediates the Increase in Blood Pressure Associated with Obesity.” Cell 159 (6): 1404–16.

Scarpace, Philip J., and Yi Zhang. 2009. “Leptin Resistance: A Prediposing Factor for Diet-Induced Obesity.” American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 296 (3): R493–500.

Martin, R. L., E. Perez, Y. J. He, R. Dawson Jr, and W. J. Millard. 2000. “Leptin Resistance Is Associated with Hypothalamic Leptin Receptor mRNA and Protein Downregulation.” Metabolism: Clinical and Experimental 49 (11): 1479–84.

Chellappa, Karthikeyani, Isaac J. Perron, Nirinjini Naidoo, and Joseph A. Baur. 2019. “The Leptin Sensitizer Celastrol Reduces Age-Associated Obesity and Modulates Behavioral Rhythms.” Aging Cell 18 (3): e12874.

Fedewa, Michael V., Elizabeth D. Hathaway, Christie L. Ward-Ritacco, Tyler D. Williams, and Ward C. Dobbs. 2018. “The Effect of Chronic Exercise Training on Leptin: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.” Sports Medicine (Auckland, N.Z.) 48 (6): 1437–50.

Peng, Jin, Lijun Yin, and Xiaohui Wang. 2021. “Central and Peripheral Leptin Resistance in Obesity and Improvements of Exercise.” Hormones and Behavior 133 (July): 105006. Peng, Jin, Lijun Yin, and Xiaohui Wang. 2021. “Central and Peripheral Leptin Resistance in Obesity and Improvements of Exercise.” Hormones and Behavior 133 (July): 105006.

Shirazi, Rozita, Vilborg Palsdottir, Jim Collander, Fredrik Anesten, Heike Vogel, Fanny Langlet, Alexander Jaschke, et al. 2013. “Glucagon-like Peptide 1 Receptor Induced Suppression of Food Intake, and Body Weight Is Mediated by Central IL-1 and IL-6.” Proceedings of the National Academy of Sciences of the United States of America 110 (40): 16199–204.

Kullmann, Stephanie, Vera Valenta, Robert Wagner, Otto Tschritter, Jürgen Machann, Hans-Ulrich Häring, Hubert Preissl, Andreas Fritsche, and Martin Heni. 2020. “Brain Insulin Sensitivity Is Linked to Adiposity and Body Fat Distribution.” Nature Communications 11 (1): 1–6.

Le Thuc, Ophélia, Katharina Stobbe, Céline Cansell, Jean-Louis Nahon, Nicolas Blondeau, and Carole Rovère. 2017. “Hypothalamic Inflammation and Energy Balance Disruptions: Spotlight on Chemokines.” Frontiers in Endocrinology 8 (August): 197.

Dorfman, Mauricio D., and Joshua P. Thaler. 2015. “Hypothalamic Inflammation and Gliosis in Obesity.” Current Opinion in Endocrinology, Diabetes, and Obesity 22 (5): 325–30.

Zhang, Xiaoqing, Guo Zhang, Hai Zhang, Michael Karin, Hua Bai, and Dongsheng Cai. 2008. “Hypothalamic IKKbeta/NF-kappaB and ER Stress Link Overnutrition to Energy Imbalance and Obesity.” Cell 135 (1): 61–73.

Valdearcos, Martin, Megan M. Robblee, Daniel I. Benjamin, Daniel K. Nomura, Allison W. Xu, and Suneil K. Koliwad. 2014. “Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function.” Cell Reports 9 (6): 2124–38.

Schur, Ellen A., Susan J. Melhorn, Seok-Kyun Oh, J. Matthew Lacy, Kathryn E. Berkseth, Stephan J. Guyenet, Joshua A. Sonnen, et al. 2015. “Radiologic Evidence That Hypothalamic Gliosis Is Associated with Obesity and Insulin Resistance in Humans.” Obesity (Silver Spring, Md.) 23 (11): 2142–48.

Pascoal, Livia B., Bruna Bombassaro, Albina F. Ramalho, Andressa Coope, Rodrigo F. Moura, Felipe Correa-da-Silva, Leticia Ignacio-Souza, et al. 2017. “Resolvin RvD2 Reduces Hypothalamic Inflammation and Rescues Mice from Diet-Induced Obesity.” Journal of Neuroinflammation 14 (1): 5.

Lee, Hannah, Thai Hien Tu, Byong Seo Park, Sunggu Yang, and Jae Geun Kim. 2019. “Adiponectin Reverses the Hypothalamic Microglial Inflammation during Short-Term Exposure to Fat-Rich Diet.” International Journal of Molecular Sciences. https://doi.org/10.3390/ijms20225738.

Herrick, Mary K., Kristin M. Favela, Richard B. Simerly, Naji N. Abumrad, and Nathan C. Bingham. 2018. “Attenuation of Diet-Induced Hypothalamic Inflammation Following Bariatric Surgery in Female Mice.” Molecular Medicine (Cambridge, Mass.) 24 (1): 56.

[1] Yi, Chun-Xia, Omar Al-Massadi, Elizabeth Donelan, Maarit Lehti, Jon Weber, Chandler Ress, Chitrang Trivedi, Timo D. Müller, Stephen C. Woods, and Susanna M. Hofmann. 2012. “Exercise Protects against High-Fat Diet-Induced Hypothalamic Inflammation.” Physiology & Behavior 106 (4): 485–90.

Berkseth, Kathryn E., Stephan J. Guyenet, Susan J. Melhorn, Donghoon Lee, Joshua P. Thaler, Ellen A. Schur, and Michael W. Schwartz. 2014. “Hypothalamic Gliosis Associated with High-Fat Diet Feeding Is Reversible in Mice: A Combined Immunohistochemical and Magnetic Resonance Imaging Study.” Endocrinology 155 (8): 2858–67.

Valdearcos, Martin, Megan M. Robblee, Daniel I. Benjamin, Daniel K. Nomura, Allison W. Xu, and Suneil K. Koliwad. 2014. “Microglia Dictate the Impact of Saturated Fat Consumption on Hypothalamic Inflammation and Neuronal Function.” Cell Reports 9 (6): 2124–38. [1] Ohlsson, L., W. Alsalim, R. D. Carr, A. Tura, G. Pacini, A. Mari, and B. Ahrén. 2013. “Glucose-Lowering Effect of the DPP-4 Inhibitor Sitagliptin after Glucose and Non-Glucose Macronutrient Ingestion in Non-Diabetic Subjects.” Diabetes, Obesity & Metabolism 15 (6): 531–37.