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The American Heart Association has identified obesity as a primary impediment to ongoing improvements in cardiovascular diseases, including hypertension. Although drugs, exercise, diets, and surgeries can each cause weight loss, few subjects maintain a reduced weight over the long term. Dysfunctional integrative control (ie, adaptation) of resting metabolic rate (RMR) appears to underlie this failed weight maintenance, yet the neurobiology of physiological and pathophysiological RMR control is poorly understood. Here, we review recent insights into the cellular and molecular control of RMR by Ang-II (angiotensin II) signaling within the arcuate nucleus of the hypothalamus. Within a unique subset of agouti-related peptide neurons, AT 1 R (Ang-II type 1 receptors) are implicated in the integrative control of RMR. Furthermore, a spontaneous G protein signal switch of AT 1 R within this neuron type appears to underlie the pathogenesis of RMR adaptation by qualitatively changing the cellular response to AT 1 R activation from a β-arrestin-1/Gαi (heterotrimeric G protein, α i subtype)-mediated inhibitory response to a Gαq (heterotrimeric G protein, α q subtype)-mediated stimulatory response. We conclude that therapeutic approaches to obesity are likely hampered by the plasticity of the signaling mechanisms that mediate the normal integrative control of energy balance. The same stimulus that would increase RMR in the normal physiological state may decrease RMR during obesity due to qualitative changes in second-messenger coupling. Understanding the mechanisms that regulate interactions between receptors such as AT 1 R and its various second messenger signaling cascades will provide novel insights into the pathogenesis of RMR adaptation and potentially point toward new therapeutic approaches for obesity and hypertension., Competing Interests: None.

Background: RGS (regulator of G protein signaling) family members catalyze the termination of G protein signaling cascades. Single nucleotide polymorphisms in the RGS2 gene in humans have been linked to hypertension, preeclampsia, and anxiety disorders. Mice deficient for Rgs2 (Rgs2 Null ) exhibit hypertension, anxiety, and altered adipose development and function., Methods: To study cell-specific functions of RGS2, a novel gene-targeted mouse harboring a conditional allele for the Rgs2 gene ( Rgs2 Flox ) was developed. These mice were bred with mice expressing Cre-recombinase via the Agouti-related peptide locus ( Agrp -Cre) to cause deletion of Rgs2 from all cells expressing Agrp (Rgs2 Agrp-KO ), or a novel transgenic mouse expressing Cre-recombinase via the ANG (angiotensin) type 1A receptor ( Agtr1a / AT 1A ) promoter encoded in a bacterial artificial chromosome (BAC-AT 1A -Cre) to delete Rgs2 in all Agtr1a -expressing cells ( Rgs2 AT1A-KO )., Results: Whereas Rgs2 Flox , Rgs2 Agrp-KO , and BAC-AT 1A -Cre mice exhibited normal growth and survival, Rgs2 AT1A-KO exhibited pre-weaning lethality. Relative to littermates, Rgs2 Agrp-KO exhibited reduced fat gains when maintained on a high fat diet, associated with increased energy expenditure. Similarly, surviving adult Rgs2 AT1A-KO mice also exhibited increased energy expenditure. Surprisingly, given the hypertensive phenotype previously reported for Rgs2 Null mice and evidence supporting a role for RGS2 in terminating AT 1A signaling in various cell types, Rgs2 AT1A-KO mice exhibited normal blood pressure, ingestive behaviors, and renal functions, both before and after chronic infusion of ANG (490 ng/kg/min, sc)., Conclusions: These results demonstrate the development of a novel mouse with conditional expression of Rgs2 and illustrate the role of Rgs2 within selected cell types for cardiometabolic control.

Obesity represents the single greatest ongoing roadblock to improving cardiovascular health. Prolonged obesity is associated with fundamental changes in the integrative control of energy balance, including the development of selective leptin resistance, which is thought to contribute to obesity-associated hypertension, and adaptation of resting metabolic rate (RMR) when excess weight is reduced. Leptin and the melanocortin system within the hypothalamus contribute to the control of both energy balance and blood pressure. While the development of drugs to stimulate RMR and thereby reverse obesity through activation of the melanocortin system has been pursued, most of the resulting compounds simultaneously cause hypertension. Evidence supports the concept that although feeding behaviors, RMR, and blood pressure are controlled through mechanisms that utilize similar molecular mediators, these mechanisms exist in anatomically dissociable networks. New evidence supports a major change in molecular signaling within AgRP (Agouti-related peptide) neurons of the arcuate nucleus of the hypothalamus during prolonged obesity and the existence of multiple distinct subtypes of AgRP neurons that individually contribute to control of feeding, RMR, or blood pressure. Finally, ongoing work by our laboratory and others support a unique role for AT 1 (angiotensin II type 1 receptor) within one specific subtype of AgRP neuron for the control of RMR. We propose that understanding the unique biology of the AT 1 -expressing, RMR-controlling subtype of AgRP neurons will help to resolve the selective dysfunctions in RMR control that develop during prolonged obesity and potentially point toward novel druggable antiobesity targets that will not simultaneously cause hypertension.

Prolonged obesity is associated with blunted feeding and thermogenic autonomic responses to leptin, but cardiovascular responses to leptin are maintained. This state of selective leptin resistance is, therefore, proposed to contribute to the pathogenesis and maintenance of obesity-associated hypertension. Cells of the arcuate nucleus of the hypothalamus detect leptin, and although the cellular and molecular mechanisms remain unclear, altered arcuate nucleus biology is hypothesized to contribute to selective leptin resistance. Male C57BL/6J mice were fed a high-fat diet (HFD) or chow from 8 to 18 weeks of age, as this paradigm models selective leptin resistance. Nuclei were then isolated from arcuate nucleus for single-nucleus RNA sequencing. HFD caused expected gains in adiposity and circulating leptin. Twenty-three unique cell-type clusters were identified, and Ingenuity Pathway Analysis was used to explore changes in gene expression patterns due to chronic HFD within each cluster. Notably, gene expression signatures related to leptin signaling exhibited suppression predominantly in neurons identified as the Agouti-related peptide ( Agrp ) subtype. Ingenuity Pathway Analysis results were also consistent with alterations in CREB (cAMP response element-binding protein) signaling in Agrp neurons after HFD, and reduced phosphorylated CREB was confirmed in arcuate nucleus after prolonged HFD by capillary electrophoresis-based Western blotting. These findings support the concept that prolonged HFD-induced obesity is associated with selective changes in Agrp neuron biology, possibly secondary to altered CREB signaling.