Appetite (hunger and satiety) is controlled by neural circuits in the brain – particularly in the hypothalamus – and their reciprocal connections to peripheral organs involved in energy metabolism (gut and liver). Understanding the structural organization of these circuits (their synaptic connections) and their neurochemistry (particularly which neurotransmitters are used at which synapses) is of fundamental importance for human health and developing new treatments for metabolic disorders such as obesity and diabetes. Neuroscientist Henning Fenselau at the Max Planck Institute and University of Cologne Germany has made several major discoveries about how food intake and energy metabolism are regulated and the consequences of abnormalities in the underlying neural circuits. Among his recent findings concern how GLP-1 in the gut communicates with the brain via the vagus nerve, and the roles of specific synaptic signals (NPY, opioids, TRH, and GABA).

LINKS

Fenselau laboratory page: https://www.sf.mpg.de/research/fenselau

GLP-1, the vagus nerve, hunger, and sugar metabolism:

https://www.cell.com/action/showPdf?pii=S1550-4131%2821%2900219-9

Synaptic amplifier of hunger:

https://pmc.ncbi.nlm.nih.gov/articles/PMC10160008/pdf/nihms-1882224.pdf

Opioids and sugar appetite

https://www-science-org.proxy1.library.jhu.edu/doi/epdf/10.1126/science.adp1510

Brainstem – amygdala circuit during fasting

https://pmc.ncbi.nlm.nih.gov/articles/PMC11211344/pdf/41467_2024_Article_49766.pdf

During vigorous exercise lactic acid (lactate) levels increase in the blood and during fasting and extended exercise the levels of the ketone BHB (b-hydroxybutyrate) increase. In this episode I talk with Stanford University professor Jonathan Long about his recent discovery that lactate and BHB in the blood are bound to the amino acid phenylalanine and that they (Lac-Phe and BHB-Phe) have beneficial effects on metabolic and brain health. Lac-Phe levels increase markedly in response to exercise in mice, humans, and race horses. Peripheral administration of Lac-Phe in suppresses food intake and reverses diet-induced obesity and insulin resistance in mice. Genetic ablation of Lac-Phe biosynthesis causes hyperphagy and obesity even in exercising mice showing a critical role for Lac-Phe in the beneficial effects of exercise. BHB-Phe has similar effects on food intake and metabolic health. We talk about the potential benefits of Lac-Phe and BHB-Phe for brain health and resilience.

LINKS

The Long laboratory webpage: https://longlabstanford.org/

Lac-Phe articles:

https://pmc.ncbi.nlm.nih.gov/articles/PMC9767481/pdf/nihms-1852727.pdf

https://pmc.ncbi.nlm.nih.gov/articles/PMC10635077/pdf/nihpp-2023.11.02.565321v1.pdf

BHB-Phe article: https://www.cell.com/action/showPdf?pii=S0092-8674%2824%2901214-5