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Mouse Microglial Calcitonin Receptor Knockout Impairs Hypothalamic Amylin Neuronal pSTAT3 Signaling but Lacks Major
Bernd Coester1, Thomas A Lutz1, Christelle Le Foll1
1Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich (UZH), 8057 Zurich, Switzerland.
Abstract:
Amylin and leptin synergistically interact in the arcuate nucleus of the hypothalamus (ARC) to control energy homeostasis. Our previous rodent studies suggested that amylin-induced interleukin-6 release from hypothalamic microglia may modulate leptin signaling in agouti-related peptide expressing neurons. To confirm the physiological relevance of this finding, the calcitonin receptor (CTR) subunit of the amylin receptor was selectively depleted in microglia by crossing tamoxifen (Tx) inducible Cx3cr1-CreERT2 mice with CTR-floxed mice. Unexpectedly, male mice with CTR-depleted microglia (KO) gained the least amount of weight of all groups regardless of diet. However, after correcting for the tamoxifen effect, there was no significant difference for body weight, fat mass or lean mass between genotypes. No alteration in glucose tolerance or insulin release was detected. However, male KO mice had a reduced respiratory quotient suggesting a preference for fat as a fuel when fed a high fat diet. Importantly, amylin-induced pSTAT3 was decreased in the ARC of KO mice but this was not reflected in a reduced anorectic response. On the other hand, KO mice seemed to be less responsive to leptin's anorectic effect while displaying similar ARC pSTAT3 as Tx-control mice. Together, these data suggest that microglial amylin signaling is not a major player in the control of energy homeostasis in mice.
Insights
Microglial amylin signaling, involving the calcitonin receptor (CTR), does not significantly impact energy homeostasis in mice. Studies found no major effects on body weight or metabolism, suggesting limited roles in appetite regulation.
Area of Science:
- Neuroendocrinology
- Metabolic Regulation
- Cellular Signaling
Background:
- Amylin and leptin are key hormones regulating energy balance through hypothalamic pathways.
- Hypothalamic microglia and interleukin-6 may mediate amylin's effects on leptin signaling.
- The calcitonin receptor (CTR) is a crucial component of the amylin receptor.
Purpose of the Study:
- To investigate the physiological role of microglial amylin signaling in energy homeostasis.
- To determine if selective depletion of CTR in microglia affects metabolic parameters and responses to leptin and amylin.
- To elucidate the contribution of microglial CTR to hypothalamic leptin signaling.
Main Methods:
- Generated microglia-specific CTR knockout (KO) mice by crossing Cx3cr1-CreERT2 with CTR-floxed mice, induced by tamoxifen (Tx).
- Assessed body weight, fat mass, lean mass, glucose tolerance, and insulin release in KO and control mice on standard and high-fat diets.
- Measured respiratory quotient, pSTAT3 activation in the arcuate nucleus (ARC), and anorectic responses to amylin and leptin.
Main Results:
- Microglial CTR depletion did not alter body weight, fat mass, or lean mass after correcting for tamoxifen effects.
- KO mice exhibited a reduced respiratory quotient on a high-fat diet, indicating increased fat utilization.
- Amylin-induced pSTAT3 in the ARC was reduced in KO mice, but anorectic responses were unaffected; leptin's anorectic effect was diminished.
Conclusions:
- Microglial amylin signaling, mediated by CTR, is not a major regulator of energy homeostasis in mice.
- While affecting fuel preference and amylin signaling pathways, microglial CTR depletion has limited impact on overall metabolic control.
- These findings suggest alternative pathways are dominant in mediating amylin and leptin actions on energy balance.
