👤 Wolfgang Baehr

Recent research suggests that the ketogenic diet (KD) has the potential to serve as an effective treatment option for neuropsychiatric disorders, targeting both dysfunctions in brain metabolism and cardiometabolic comorbidities. In many patients, KDs may ameliorate comorbidities such as obesity, metabolic syndrome and type 2 diabetes. However, the long-term effects of KDs on cardiovascular health remain an important topic of investigation, due to considerable inter-individual variability in how KDs may impact lipid metabolism. While some studies have shown no significant change in cholesterol levels, and some have shown improvements, still others have highlighted the potential of KDs to induce or exacerbate hyperlipidemia. To shed new light on this ongoing controversy, we present both beneficial and concerning effects of a 3-month intervention with Ketogenic Metabolic Therapy (KMT) (1.5:1 ratio) on a wide range of cardiometabolic health markers in seven outpatients with bipolar disorder and comorbid dyslipidemia. Cardiometabolic assessments were based on markers of lipoprotein burden, such as apolipoprotein B (apoB), lipoprotein (a) (Lp(a)), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG) and total cholesterol (TC), markers of inflammation, such high-sensitivity C-reactive protein (hsCRP) and tumor necrosis factor (TNF-α), markers of oxidative stress, such as malondialdehyde-modified LDL (MDA-LDL) and nitrotyrosine, molecules that relate to endothelial function, such as homocysteine and advanced glycation end products (AGE), and anthropometric measures, such as BMI and fat mass. Mean changes between pre-KMT and post-KMT measurements were calculated. In addition, within-person changes in outcomes of interest were visually summarized using boxplots. Beneficial cardiometabolic effects included a decrease in mean Lp(a) of 6.6 mg/dl (-21%), a reduction in mean triglyceride of 40.6 mg/dl (-30%), a reduction in mean apoB of 0.14 g/L (-10,5%) and an increase in mean HDL-C of 3 mg/dL (+5%), a reduction in mean hsCRP of 0.94 mg/L (-45%), a reduction in mean TNF-α of 1.31 pg/ml (-7%), a reduction in mean MDA-LDL of 36.77 U/L (-38%), a reduction in mean nitrotyrosine of 225 nmol/L (-28%), a mean weight reduction of 4 kg (-4,6%), a mean visceral fat reduction of 0.69% (-10%) and a mean fat mass reduction of 3.7 kg (-12%). However, some concerning effects were also observed. Of note, mean homocysteine levels increased by 1.94 umol/L (+18%) and mean AGE levels increased by 30.9 ug/ml (+106%). Moreover, mean LDL-C was increased by 14 mg/dl (+9%) and mean total cholesterol was increased by 7 mg/dl (+3%). Based on these findings, it is concluded that comprehensive Ketogenic Metabolic Therapy provided to outpatients with bipolar disorder can be beneficial in improving a broad range of cardiometabolic health markers, including lipid metabolism, inflammation, oxidative stress and anthropometric measures. Tentatively, these findings suggest that at least a proportion of patients with bipolar disorder may find remarkable improvements in cardiometabolic health adopting a metabolic treatment such as the ketogenic diet. However, potentially concerning effects on markers such as homocysteine and AGE call for well-formulated, individualized KDs. Show less

UNC119 proteins are involved in G protein trafficking in mouse retinal photoreceptors and Caenorhabditis elegans olfactory neurons. An Unc119 null allele is associated with cone-rod dystrophy in mouse, but the mechanism leading to disease is not understood. We studied the role of Unc119 paralogs and Arl3l2 in zebrafish vision and retinal organization resulting from unc119c and arl3l2 knockdown. Zebrafish unc119c was amplified by PCR from retina and pineal gland cDNA. Its expression pattern in the eye and pineal gland was determined by whole-mount in-situ hybridization. unc119c and arl3l2 were knocked down using morpholino-modified oligonucleotides (MO). Their visual function was assessed with a quantitative optomotor assay on 6 days post-fertilization larvae. Retinal morphology was analyzed using immunohistochemistry with anti-cone arrestin (zpr-1) and anti-cone transducin-α (GNAT2) antibodies. The zebrafish genome contains four genes encoding unc119 paralogs located on different chromosomes. The exon/intron arrangements of these genes are identical. Three Unc119 paralogs are expressed in the zebrafish retina, termed Unc119a-c. Based on sequence similarity, Unc119a and Unc119b are orthologs of mammalian UNC119a and UNC119b, respectively. A third, Unc119c, is unique and not present in mammals. Whole mount in-situ hybridization revealed that unc119a and unc119b RNA are ubiquitously expressed in the CNS, and unc119c is specifically expressed in photoreceptive tissues (pineal gland and retina). A Unc119 interactant, Arl3l2 also localizes to the pineal gland and the retina. As measured by the optomotor response, unc119c and arl3l2 knockdown resulted in significantly lower vision compared to wild-type zebrafish larvae and control morpholino (MO). Immunohistological analysis with anti-cone transducin and anti-cone arrestin (zpr-1) indicates that knockdown of unc119c leads to photoreceptor degeneration mostly affecting cones. Our results suggest that Unc119c is the only Unc119 paralog that is highly specific to the retina in zebrafish. Unc119c and Arl3l2 proteins are important for the function of cones. Show less