Targeted Apoptosis of the Angiotensin AT1R (Agtr1a)-Expressing Subtype of Agouti-Related Peptide Neurons in Adult Mice Increases Food Intake and Resting Metabolism, and Alters Blood Pressure Control

Background: Neurons of the hypothalamic arcuate nucleus that express Agouti-related peptide (AgRP) have been implicated in control of energy intake and expenditure. Recently we discovered that subtypes of AgRP neurons can be distinguished based upon expression of angiotensin II receptors. The Type 1 subtype is inhibited via the angiotensin type 1 receptor (AT1R / Agtr1a). We hypothesized that ablation of Type 1 AgRP neurons would have long-term consequences on energy balance. Methods: Young adult mice expressing Cre-recombinase via the Agtr1a locus received bilateral microinjection of an AAV vector encoding Cre-dependent expression of caspase-3 into the arcuate nucleus. An array of cardiometabolic phenotypes were then serially evaluated in mice housed at 22°C or 30°C. Results: Ablation of Type 1 AgRP neurons caused increased food intake, adiposity, resting metabolic rate via a mechanism involving hepatic function and nutrient partitioning, increased preferred ambient temperature, progressive loss of core temperature defense, and changes in the relationship between blood pressure and heart rate. Many phenotypes were ameliorated by housing animals at thermoneutrality. Conclusions: The Type 1 AgRP neuron influences cardiometabolic control through modulation of thermoregulatory responses to cold. Some functions of Type 1 AgRP neurons appear to oppose canonical roles of other AgRP neuron subtypes. Overall design: Cell-specific ablation of Type 1 AgRP neurons was achieved by injecting an Adeno-associated virus (AAV) encoding Cre-activatable Caspase3 into the ARC of adult AT1RCRE mice that express Cre-recombinase via the AT1R locus. Male and female ablated and control mice were housed at either 22°C or 30°C from time of surgery. Two weeks after surgery, liver samples were snap frozen for future processing.