Mitochondrial retrograde signaling connects respiratory capacity to thermogenic gene expression

Mitochondrial respiration plays a crucial role in determining the metabolic state of brown adipose tissue (BAT), due to its direct roles in thermogenesis, as well as through additional mechanisms. Here, we show that respiration-dependent retrograde signaling from mitochondria to nucleus contributes to genetic and metabolic reprogramming of BAT. In mouse BAT, ablation of LRPPRC (LRP130), a potent regulator of mitochondrial transcription and respiratory capacity, triggers down-regulation of thermogenic genes, promoting a storage phenotype in BAT. This retrograde regulation functions by inhibiting the recruitment of PPARgamma to the regulatory elements of thermogenic genes. Reducing cytosolic Ca2+ reverses the attenuation of thermogenic genes in brown adipocytes with impaired respiratory capacity, while induction of cytosolic Ca2+ is sufficient to attenuate thermogenic gene expression, indicating that cytosolic Ca2+ mediates mitochondria-nucleus crosstalk. Our findings suggest respiratory capacity governs thermogenic gene expression and BAT function via mitochondria-nucleus communication, which in turn leads to either a thermogenic or storage mode

Involvement of SIK3 in Glucose and Lipid Homeostasis in Mice

Salt-inducible kinase 3 (SIK3), an AMP-activated protein kinase-related kinase, is induced in the murine liver after the consumption of a diet rich in fat, sucrose, and cholesterol. To examine whether SIK3 can modulate glucose and lipid metabolism in the liver, we analyzed phenotypes of SIK3-deficent mice. Sik3−/− mice have a malnourished the phenotype (i.e., lipodystrophy, hypolipidemia, hypoglycemia, and hyper-insulin sensitivity) accompanied by cholestasis and cholelithiasis. The hypoglycemic and hyper-insulin-sensitive phenotypes may be due to reduced energy storage, which is represented by the low expression levels of mRNA for components of the fatty acid synthesis pathways in the liver. The biliary disorders in Sik3−/− mice are associated with the dysregulation of gene expression programs that respond to nutritional stresses and are probably regulated by nuclear receptors. Retinoic acid plays a role in cholesterol and bile acid homeostasis, wheras ALDH1a which produces retinoic acid, is expressed at low levels in Sik3−/− mice. Lipid metabolism disorders in Sik3−/− mice are ameliorated by the treatment with 9-cis-retinoic acid. In conclusion, SIK3 is a novel energy regulator that modulates cholesterol and bile acid metabolism by coupling with retinoid metabolism, and may alter the size of energy storage in mice

Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line

Memantine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, and is an approved drug for the treatment of moderate-to-severe Alzheimer’s disease. We identified a mouse strain with a naturally occurring mutation and an ataxic phenotype that presents with severe leg cramps. To investigate the phenotypes of these mutant mice, we screened several phenotype-modulating drugs and found that memantine (10 mg/kg) disrupted the sense of balance in the mutants. Moreover, the mutant mice showed an attenuated optokinetic response (OKR) and impaired OKR learning, which was also observed in wild-type mice treated with memantine. Microsatellite analyses indicated that the Grid2 gene-deletion is responsible for these phenotypes. Patch-clamp analysis showed a relatively small change in NMDA-dependent current in cultured granule cells from Grid2 gene-deleted mice, suggesting that GRID2 is important for correct NMDA receptor function. In general, NMDA receptors are activated after the activation of non-NMDA receptors, such as AMPA receptors, and AMPA receptor dysregulation also occurs in Grid2 mutant mice. Indeed, the AMPA treatment enhanced memantine susceptibility in wild-type mice, which was indicated by balance sense and OKR impairments. The present study explores a new role for GRID2 and highlights the adverse effects of memantine in different genetic backgrounds

<i>Sik3</i>^−/− mice are lean, hypolipidemic, and hypoglycemic.

<p>(A) C57BL/6 mice (male: n = 4) were fed various diets (HF, high fat; HS, high sucrose; HChol, high cholesterol) for 2 weeks, and liver mRNA was examined by quantitative PCR. *, **, and *** indicate <i>p</i><0.05, <0.01, and <0.001, respectively. Means and SEM are shown. (B) The body weight of male mice (n = 6) was monitored. All data points show <i>p</i><0.001. (C) One-year-old male mice (n = 5) were sacrificed (scale: 1 mm), and the indicated tissues were weighed (D). (E) Histology of liver and mesenteric fatty tissue is shown. Each magnification is the same. (F) Cholesterol (Chol) and triglycerides (TG) in the liver and serum were measured (n = 5). (G) Serum cholesterol and TG were separated using FPLC. (H) The food consumption of each group (n = 12). (I) Rectal temperature (n = 12). (J) Oxygen consumption (VO₂, voluntarily O₂ consumption) and (K) average respiratory quotient (RQ) during the day and night (n = 5). (L) Mice (n = 5) were fasted and their blood glucose levels were monitored at the indicated time points. All data points show <i>p</i><0.001. (M) After 4-h fasting, the serum levels of insulin, leptin, free fatty acid (FFA), and ß-hydroxybutyrate were measured. (N) After 4-h fasting, glucose (1.5 g/kg) was intraperitoneally injected (GTT, glucose tolerance test) and blood glucose levels were monitored (n = 5). (O) After 24-h fasting, lactate (1.5 g/kg) was injected intraperitoneally (LTT, lactate tolerance test; n = 5).</p

Cholesterol accumulation in the livers of <i>Sik3</i>^−/− mice after feeding with a high-cholesterol diet.

<p>(A) Male mice were fed a 2% cholesterol diet for 4 months (12–30 weeks) and then sacrificed (n = 5). (B) HE staining of the liver (sets at the <i>upper</i> and <i>lower left</i>). The arrows indicate eosin-negative foci which with autofluorescence (<i>lower right</i>: red, and nuclei are blue (DAPI)). The magnification is the same in each set. (C) Cholesterol and TG levels in the liver and serum were measured (n = 5). *** indicates <i>p</i><0.001. Means and SEM are shown. (D) FPLC analysis of serum lipids. (E) Serum levels of alanine aminotransferase (ALT) were monitored at the indicated time points. * and ** indicate <i>p</i><0.05 and <i>p</i><0.01, respectively. (F) Quantitative polymerase chain reaction analysis of inflammatory molecules in the liver.</p