Researchers from the National Institutes of Health observed that lowered cyclic AMP-dependent protein kinase A (PKA) dendritic activity resulted in a decreased consumption of palatable foods and increased motivation for exercise. These findings were published in The Journal of Clinical Investigation: Insight.

Mice that had an interruption of the ubiquitously expressed PKA (RIIa knock out [RIIaKO]) or were wild type (WT) were analyzed for this study. Mice were assessed for feeding behaviors when given a high fat diet (HFD; 5.49 kcal/g) for 3 weeks, sucrose (10% w/v) intake and preference over 3 weeks, operant conditioning with positive reinforcement, and voluntary running behavior over 2 weeks. Mouse brains were dissected and analyzed for PKA enzymatic activity.

The habenula (Hb) of RIIaKO mice showed significantly reduced PKA enzymatic activity (P <.001) despite no change in PKA activity in the prefrontal cortex and striatum which provides direct inputs into the Hb. Compared with WT, the acetylcholine concentrations were significant decreased in the Hb (P <.05) and interpeduncular nucleus (P <.01) of RIIaKO brains.


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Compared with WT, the RIa protein levels tended to be reduced and the Ca protein levels were significantly lower (P <.05) among the RIIaKO mice Hb lysates. The catalytic a, b, and g protein levels were also lower among RIIaKO Hb.

PKA localization in dendrites of RIIaKO mice was severely impaired and total catalytic subunit expression decreased. No PKA localization in the cytoplasm was observed among the knock-out mice.

Female RIIaKO mice presented with the HFD consumed less energy (11.76±0.33 kcal/g by weight [BW]) than the WT mice (13.50±0.51 kcal/g BW; P =.0091). This pattern was not observed among the male mice. Female RIIaKO mice gained the least amount of weight (P =.059) over the study period.

Following a 14-hour fast, RIIaKO mice spent less time (P <.01) interacting with a food-reward task, earned fewer reward pellets (P <.05), and had a lower breakpoint (P <.05).

Following the first day presented with a sucrose solution, RIIaKO mice consumed lower levels of sucrose than the WT mice (female: P =.0095, male: P =.0053). Male RIIaKO mice had a significantly lower preference for the sucrose (P =.0073).

RIIaKO mice ran 2-3 times the distance compared with their WT littermates (female: P <.01, male: P <.0001). Compared with male RIIa+/- mice, male RIIaKO mice had significantly more total wheel turns (P <.001). When the running wheel was blocked, c-Fos (P <.0001) and c-Jun (P <.01) expression were increased, suggesting a stress or anxiety response to withholding exercise.

This study was limited by not including cell-specific data, warranting further study.

These data indicated that decreasing PKA activity, mediated through the Hb, reduced desires for palatable foods and facilitated motivation for increased physical activity.

Reference

London E, Wester JC, Bloyd M, Bettencourt S, McBain CJ, Stratakis CA. Loss of habenular Prkar2a reduces hedonic eating and increases exercise motivation. JCI Insight. 2020;5(23):141670. doi:10.1172/jci.insight.141670