Metabolic disease: Blocking brain enzyme curbs appetite

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Ca²⁺/calmodulin-dependent protein kinase kinase 2 (CAMKK2) forms a stable signaling complex with an AMPK alpha / beta heterodimer and has a key role in appetite control and normal glucose responses.

Altered hypothalamic neuronal responses to hormonal and nutrient signals have been implicated in the pathophysiology of obesity and diabetes. Writing in Cell Metabolism, Anderson and colleagues identify a specific kinase — CAMKK2 — to be involved in regulating one of these signalling pathways, and demonstrate that blockade of its activity may prove to be a novel therapeutic strategy.


CORBIS

Ghrelin is a hormone produced in the stomach that stimulates food intake by inducing hypothalamic release of the orexigenic hormone, neuropeptide Y (NPY). AMP-dependent protein kinase (AMPK) is a key signalling component in the ghrelin–NPY pathway, and its activity is dependent on its phosphorylation by an upstream kinase (AMPKK). Recent studies in mammalian cells have indicated Ca²⁺/calmodulin-dependent protein kinase kinase 2 (CAMKK2) to be a physiologically relevant AMPKK, which is expressed throughout the brain.

The authors therefore first aimed to determine whether CAMKK2 is a component of the ghrelin signalling pathway. They confirmed that CAMKK2 is highly expressed in the hypothalamus of mice, where it was largely restricted to the arcuate nucleus and tracked with NPY neurons. They next developed mice lacking CAMKK2 (Camkk2-null) and noted that AMPK activity and NPY levels were decreased in these mice. Furthermore, while ghrelin administration increased food intake in control mice, it had no such effect in Camkk2-null mice, consistent with diminished ghrelin–NPY signalling.

The authors then set out to obtain more direct evidence linking CAMKK2, AMPK and NPY production. When a mouse hypothalamic cell line was treated with ionomycin (to increase intracellular Ca²⁺), CAMKK2 levels were increased, AMPK was phosphorylated and NPY levels were increased. These effects were blocked by the selective CAMKK2 inhibitor, STO-609. Further studies demonstrated that CAMKK2 forms a stable signalling complex with an AMPK alpha / beta heterodimer.

Finally, they confirmed a role of CAMKK2 in appetite control and highlighted its potential as a therapeutic target. As observed with NPY-depleted mice, Camkk2-null mice ate less than control mice following a 48 hour fast. In addition, STO-609 decreased food intake, induced weight loss and decreased NPY levels in control mice. Importantly, Camkk2-null mice were resistant to the effects of a high-fat diet: over a 31-week time-course they gained less body weight than control mice, and displayed reduced average daily food intake and adiposity. Furthermore, while control mice became intolerant to glucose and developed insulin resistance, Camkk2-null mice retained normal glucose responses.

Owing to poor expression of CAMKK2 in other tissues — and LKB1 already having been identified as the important AMPKK in peripheral metabolic tissues — effects of CAMKK2 blockade are likely to be brain-specific. Overall, these results indicate that targeting CAMKK2 has promise as a strategy to both improve glucose tolerance and promote weight loss — a potential advantage over most other current drugs for type 2 diabetes, which promote weight gain.

Sarah Crunkhorn

References

Anderson, K. et al. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 7, 377–388 (2008) | Article | PubMed |