Conditional genetic deletion of Grk2 from AgRP neurons resulted in smaller body size in female mice compared to littermate controls by 4 weeks of age (p<0.01).
Grk2 within AgRP neurons plays a role in the integrative control of energy balance, with effects potentially more pronounced in females.
p-value: p=< 0.01
Agouti-Related Peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARC) are vital for integrative control of feeding and energy expenditure. A subset of AgRP neurons (“Type 1”) expresses the angiotensin II type 1 receptor (AT1R) and is critical for the integrative control of resting metabolic rate (RMR). In these cells, AT1R normally couples to Gi to inhibit the cell, but obesity induces a G protein ‘signal switch’ whereby AT1R stops inhibiting the cell via Gi and instead starts stimulating the cell via Gq. This signal switch fundamentally alters the integrative control of RMR during obesity. The objective of our ongoing work is to understand the molecular mediators of AT1R signal switching, to identify novel therapeutic targets to reverse changes in RMR control that occur during obesity. G protein-coupled Receptor Kinases (GRKs) modulate phosphorylation of the C-terminal tail of receptors such as AT1R, thereby dictating second messenger recruitment in other tissues. GRK2 and GRK3 represent one subfamily of GRKs with potentially overlapping functions that are implicated specifically in the actions of AT1R in other tissues, and GRK5 and GRK6 represent a distinct subfamily. Thus, we hypothesized a role for GRKs in AT1R signal switching in Type 1 AgRP neurons during obesity. Analysis of a new spatial transcriptomic dataset of the mouse ARC after 10wk diet-induced obesity (n=3m vs 3m) indicated that Grk2 was the most highly expressed Grk in AgRP neurons, followed by Grk3. In contrast, Grk5 and Grk6 were expressed at notably lower levels in these cells. Further, although no change in Grk2 or Grk3 mRNA levels were observed with obesity, 10 wk of high fat diet (HFD; D12451, 45% kcal from fat) caused a significant increase in Grk2 protein, but no change in GRK3 protein, within the ARC (n=7m vs 7m, p< 0.05) as assessed via JESS capillary electrophoresis-based Western blotting. We then generated mice with conditional genetic deletion of Grk2 from AgRP neurons (Grk2Agrp-KO) to test the functional significance of Grk2 in AgRP cells. Female Grk2Agrp-KO mice were smaller than littermate controls already by 4 wk of age (n=16 vs 13, p< 0.01), though only a non-significant trend was observed in males (n=11 vs 17, p=0.08). Relative body composition (i.e., fat %) was similar across all groups. Together, these findings support a role for Grk2 within AgRP neurons in the integrative control of energy balance, and these effects may be more pronounced in females. Ongoing experiments include (i) comprehensive metabolic phenotyping to understand the complex effects Grk2 manipulation in AgRP neurons has upon feeding and energy expenditure, (ii) selective conditional deletion of Grk2 only from the Type 1 subtype of AgRP neuron to more specifically understand its function in this cell subtype, and (iii) conditional genetic manipulation of Grk3 alone or both Grk2+Grk3 simultaneously to clarify potential compensatory actions of these subfamily members in AgRP neurons. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Hole et al. (Fri,) conducted a other in Obesity (n=77). Conditional genetic deletion of Grk2 from AgRP neurons (Grk2Agrp-KO) vs. Littermate controls was evaluated on Body size (p=< 0.01). Conditional genetic deletion of Grk2 from AgRP neurons resulted in smaller body size in female mice compared to littermate controls by 4 weeks of age (p<0.01).