Adiponectin receptor 1 (ADIPOR1) is a lipid and glucose metabolism regulator that possesses intrinsic ceramidase activity. Mutations of the ADIPOR1 gene have been associated with non-syndromic and syndromic retinitis pigmentosa. Here we show that the absence of AdipoR1 in mice leads to progressive photoreceptor degeneration, significant reduction of electroretinogram amplitudes, decreased retinoid content in the retina, and reduced cone opsin expression. Single-cell RNA-Seq results indicated that ADIPOR1 encodes the most abundantly expressed ceramidase in mice and one of the two most highly expressed ceramidases in the human retina, next to acid ceramidase ASAH1. We discovered an accumulation of ceramides in the AdipoR1 -/retina, likely due to insufficient ceramidase activity for healthy retina function, resulting in photoreceptor death. Combined treatment with desipramine and L-cycloserine (DC) lowered ceramide levels and exerted a protective effect on photoreceptors in AdipoR1 -/mice. Moreover, we observed improvement in cone-mediated retinal function in the DC-treated animals. Lastly, we found that prolonged DC-treatment corrected the electrical responses of the primary visual cortex to visual stimuli, approaching near-normal levels for some parameters.These results highlight the importance of ADIPOR1 ceramidase in the retina, and show that pharmacological inhibition of ceramide generation can provide a therapeutic strategy for ADIPOR1-related retinopathy.

The primary goal of this study was to determine whether the striate cortex (Oc 1) of the guinea pig projects to the pretectal nucleus of the optic tract (NOT), the first postretinal station of the horizontal optokinetic pathway, and, if so, to analyze the anatomical organization of this cortico-NOT projection. Other goals of this investigation are to identify other pretectal nuclear projections from the visual cortex in the guinea pig, and to determine whether there is any visuotopic organization in this pathway. Axonal tracers (biocytin or 3H-leucine) were injected into the striate cortex (Oc 1), and the tissue processed with histochemical or light autoradiographic techniques. All subcortical terminal labeling is ipsilateral in the basal ganglia and thalamic nuclei. Furthermore, projections are traced to the ipsilateral brainstem, including two areas of the pretectal complex: (1) one in the NOT, extending in some cases to the adjacent lateral portion of the posterior pretectal nucleus (PPN), and (2) one in the pars compacta of the anterior pretectal nucleus (APNc). The terminal fields in the APN are consistently located rostrally in the dorsolateral portion of the nucleus, independently of the injection site in Oc 1, whereas in the NOT the terminal fields shift slightly after injections placed in different locations in the striate cortex. A correlation of the injection sites in Oc 1 and terminal fields in the NOT reveals a loose topographic organization in the cortico-NOT projection; accordingly, the rostrocaudal axis of the striate cortex projects to the lateromedial axis of the NOT, with a 90 degrees rotation, whereas lateral parts of the striate cortex project diffusely throughout the rostrocaudal extent of the NOT. These data show for the first time that the NOT in the guinea pig receives a substantial projection from the visual cortex. Given the fact that in the guinea pig the optokinetic nystagmus shares some of the characteristics found in cat and monkey (i.e., consistent initial fast rise in the slow phase velocity and reduced asymmetry in monocular stimulation), the present findings lend support to the hypothesis that a cortical input to the NOT is a necessary condition for these oculomotor properties to be present.

Lipids participate in all cellular processes. Diverse methods have been developed to investigate lipid composition and distribution in biological samples to understand the effect of lipids across an organism’s lifespan. Here, we summarize the advanced techniques for studying lipids, including mass spectrometry-based lipidomics, lipid imaging, chemical-based lipid analysis and lipid engineering and their advantages. We further discuss the limitation of the current methods to gain an in-depth knowledge of the role of lipids in aging, and the possibility of lipid-based therapy in aging-related diseases.

Insulin resistance contributed to the development of type 2 diabetes (T2D) and is a major risk factor for diabetic cardiomyopathy (DCM). We have previously reported that insulin resistance led to impaired Akt1 translocation into myocardial mitochondria in DCM. To study the role of mitochondrial Akt1 in DCM, we have generated two cardiac-specific inducible Cre-lox transgenic mice models that expresses (1) a mitochondria-targeting dominant negative Akt (CAMDAKT) or (2) a mitochondria-targeting constitutively active Akt (CAMCAKT) upon Tamoxifen induction (T). T-CAMDAKT mice showed LV dysfunction with increased heart failure markers, while T-CAMCAKT mice restored LV dysfunction to normal in the T2D model. In a T2D model induced by high fat/high fructose diet with relative insulin deficiency, T-CAMCAKT mice showed lower body fat mass (16.6% vs. 26.5%, p<0.001) and higher body lean mass (77.1% vs. 68.1%, p<0.001). To study the mechanism underlying the changes of body composition, we performed transcriptomic profiling and analysis in gonadal white adipose tissues (WAT) by bulk RNA sequencing. When compared to the control T2D mice, 544 genes were upregulated and 1077 genes were downregulated in the WAT of T-CAMCAKT T2D mice. The result indicated enhanced lipid catabolism, triglyceride catabolism, HDL assembly, and downregulated critical nuclear transcription. Pathway analysis revealed the Liver X receptor/Retinoid X receptor signaling was activated in WAT of T-CAMCAKT mice as compared to the controls. This was accompanied by increased fatty acid oxidation and apolipoproteins expression. These findings suggest that impaired mitochondrial Akt signaling in DCM could remotely increase adiposity by reducing lipid catabolism in WAT through modulating LXR/RXR signaling. Disclosure Y. Chen: None. A. Ta: None. E. Tom: None. Y. Chen: None. P.H. Wang: Board Member; Self; Dianavi. Funding National Institutes of Health (R01HL096987)

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