RIIß-PKA in GABAergic Neurons of Dorsal Median Hypothalamus Governs White Adipose Browning.

The RIIß subunit of  cAMP-dependent protein kinase A (PKA) is expressed in the brain and adipose tissue. RIIß-knockout mice show leanness and increased UCP1 in brown adipose tissue. The authors have previously reported that RIIß reexpression in hypothalamic GABAergic neurons rescues the leanness. However, whether white adipose tissue (WAT) browning contributes to the leanness and whether RIIß-PKA in these neurons governs WAT browning are unknown. Here, this work reports that RIIß-KO mice exhibit a robust WAT browning. RIIß reexpression in dorsal median hypothalamic GABAergic neurons (DMH GABAergic neurons) abrogates WAT browning. Single-cell sequencing, transcriptome sequencing, and electrophysiological studies show increased GABAergic activity in DMH GABAergic neurons of RIIß-KO mice. Activation of DMH GABAergic neurons or inhibition of PKA in these neurons elicits WAT browning and thus lowers body weight. These findings reveal that RIIß-PKA in DMH GABAergic neurons regulates WAT browning. Targeting RIIß-PKA in DMH GABAergic neurons may offer a clinically useful way to promote WAT browning for treating obesity and other metabolic disorders.

Hypothalamic PKA regulates leptin sensitivity and adiposity.

Mice lacking the RIIß regulatory subunit of cyclic AMP-dependent protein kinase A (PKA) display reduced adiposity and resistance to diet-induced obesity. Here we show that RIIß knockout (KO) mice have enhanced sensitivity to leptin's effects on both feeding and energy metabolism. After administration of a low dose of leptin, the duration of hypothalamic JAK/STAT3 signalling is increased, resulting in enhanced POMC mRNA induction. Consistent with the extended JAK/STAT3 activation, we find that the negative feedback regulator of leptin receptor signalling, Socs3, is inhibited in the hypothalamus of RIIß KO mice. During fasting, RIIß-PKA is activated and this correlates with an increase in CREB phosphorylation. The increase in CREB phosphorylation is absent in the fasted RIIß KO hypothalamus. Selective inhibition of PKA activity in AgRP neurons partially recapitulates the leanness and resistance to diet-induced obesity of RIIß KO mice. Our findings suggest that RIIß-PKA modulates the duration of leptin receptor signalling and therefore the magnitude of the catabolic response to leptin.

Olive oils modulate fatty acid content and signaling protein expression in apolipoprotein E knockout mice brain.

Atherosclerosis contributes to disruption of neuronal signaling pathways by producing lipid-dependent modifications of brain plasma membranes, neuroinflammation and oxidative stress. We investigated whether long-term (11 weeks) consumption of refined- (ROO) and pomace- (POO) olive oil modulated the fatty acid composition and the levels of membrane signaling proteins in the brain of apolipoprotein E (apoE) knockout (KO) mice, an animal model of atherosclerosis. Both of these oils are rich in bioactive molecules with anti-inflammatory and antioxidant effects. ROO and POO long-term consumption increased the proportion of monounsaturated fatty acids (MUFAs), particularly of oleic acid, while reducing the level of the saturated fatty acids (SFAs) palmitic and stearic acid. As a result, the MUFA:SFA ratio was higher in apoE KO mice brain fed with ROO and POO. Furthermore, both oils reduced the level of arachidonic and eicosapentaenoic acid, suggesting a decrease in the generation of pro- and anti-inflammatory eicosanoids. Finally, ROO and POO induced an increase in the density of membrane proteins implicated in both the Galphas/PKA and Galphaq/PLCbeta1/PKCalpha signaling pathways. The combined effects of long-term ROO and POO consumption on fatty acid composition and the level of signaling proteins involved in PKA and PKC activation, suggest positive effects on neuroinflammation and brain function in apoE KO mice brain, and convert these oils into promising functional foods in diseases involving apoE deficiency.