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Biology subjects

Karolczak, E. O.

Publications and source records attributed to Karolczak, E. O..

3 recordsLinked to original sources

A simple action reduces food intake and obesity in mice

Diets that are high in fat cause over-eating and weight gain in multiple species of animals, suggesting that high dietary fat is sufficient to cause obesity. However, high-fat diets are typically provided freely to animals in obesity experiments, so it remains unclear if high-fat diets would still cause obesity if they required more effort to obtain. We hypothesized that unrestricted and easy access is necessary for high-fat diet induced over-eating, and the corollary that requiring mice to perform small amounts of work to obtain high-fat diet would reduce high-fat diet intake and associated weight gain. To test this hypothesis, we developed a novel home-cage based feeding device that either provided high-fat diet freely, or after mice poked their noses into a port one time - a simple action that is easy for them to do. We tested the effect of this intervention for six weeks, with mice receiving all daily calories from high-fat diet, modifying only how they accessed it. Requiring mice to nose-poke to access high-fat diet reduced intake and nearly completely prevented the development of obesity. In follow up experiments, we observed a similar phenomenon in mice responding for low-fat grain-based pellets that do not induce obesity, suggesting a general mechanism whereby animals engage with and consume more food when it is freely available vs. when it requires a simple action to obtain. We conclude that unrestricted access to food promotes overeating, and that a simple action such as a nose-poke can reduce over-eating and weight gain in mice. This may have implications for why over-eating and obesity are common in modern food environments, which are often characterized by easy access to low-cost unhealthy foods.

animal behavior and cognition↗

A Hypothalamic Circuit that Modulates Feeding and Parenting Behaviors

Across mammalian species, new mothers undergo considerable behavioral changes to nurture their offspring and meet the caloric demands of milk production1-5. While many neural circuits underlying feeding and parenting behaviors are well characterized6-9, it is unclear how these different circuits interact and adapt during lactation. Here, we characterized the transcriptomic changes in the arcuate nucleus (ARC) and the medial preoptic area (MPOA) of the mouse hypothalamus in response to lactation and hunger. Furthermore, we showed that heightened appetite in lactating mice was accompanied by increased activity of hunger-promoting agouti-related peptide (AgRP) neurons in the ARC. To assess the strength of hunger versus maternal drives, we designed a conflict assay where female mice chose between a food source or a chamber containing pups and nesting material. Although food-deprived lactating mothers prioritized parenting over feeding, hunger reduced the duration and disrupted the sequences of parenting behaviors in both lactating and virgin females. We discovered that ARCAgRP neurons directly inhibit bombesin receptor subtype-3 (BRS3) neurons in the MPOA, a population that governs both parenting and satiety. Selective activation of this ARCAgRP to MPOABRS3 circuit shifted behaviors from parenting to food-seeking. Thus, hypothalamic networks are modulated by physiological states and work antagonistically during the prioritization of competing motivated behaviors.

neuroscience↗

Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety

Liraglutide and other agonists of the glucagon-like peptide 1 receptor (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons which inhibit hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nuclei transcriptomics. Applying this method to AgRP neurons predicted at least 21 afferent subtypes in the mouse mediobasal and paraventricular hypothalamus. Among these are Trh+ Arc neurons (TrhArc), inhibitory neurons which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TrhArc neurons inhibits AgRP neurons and feeding in an AgRP neuron-dependent manner. Silencing TrhArc neurons causes over-eating and weight gain and attenuates liraglutides effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons, and reveal a circuit through which GLP-1RAs suppress appetite.

neuroscience↗