Czyzyk, Traci A.

AbstractMPZL3 is a nuclear‐encoded, mitochondrially localized, immunoglobulin‐like V‐type protein that functions as a key regulator of epithelial cell differentiation, lipid metabolism, ROS production, glycemic control, and energy expenditure. Recently, MPZL3 has surfaced as an important modulator of sebaceous gland function and of hair follicle cycling, an organ transformation process that is also governed by peripheral clock gene activity and PPARγ. Given the phenotype similarities and differences between Mpzl3 and Pparγ knockout mice, we propose that MPZL3 serves as a signaling hub that is regulated by core clock gene products and/or PPARγ to translate signals from these nuclear transcription factors to the mitochondria to modulate circadian and metabolic regulation. Conservation between murine and human MPZL3 suggests that human MPZL3 may have similarly complex functions in health and disease. We summarize current knowledge and discuss future directions to elucidate the full spectrum of MPZL3 functions in mammalian physiology.

Binge eating disorder (BED) affects approximately 3% of adults in the USA and is characterized by repeated episodes of eating unusually large amounts of food in a short period of time without engaging in compensatory behaviors. Interestingly, a significant comorbidity with substance abuse exists in patients with BED. Opioid peptides are known to regulate appetitive behavior. Moreover, opioid receptor antagonists (OpRA) are used clinically in the treatment of alcohol and substance abuse. In both rats and mice, the pan OpRA LY255582 was effective in reducing BE at doses that did not affect control 24 hour intake. In rats, similar reductions in BE were observed using the mu and delta selective OpRAs LY2491481 and naltriben, respectively. The kappa selective OpRA LY2444296 was ineffective in reducing BE in rats. In order to confirm our pharmacology findings using genetic models, we evaluated BE in OpR knockout mice using a similar intermittent access paradigm. Unlike our antagonist studies, no differences in BE were observed in either the mu or delta receptor mutants compared to wildtypes. Interestingly, spontaneous free access feeding and BE were increased in the kappa receptor specific and mu‐delta‐kappa combinatorial mutants in comparison to wildtypes. Our data support that endogenous opioids modulate BE in a complex manner in rodents.

Nagarse (N) is traditionally used to isolate mitochondria (mito) from skeletal muscle (SM). We investigated the effects of N on functional parameters of mechanically liberated mito. Mito from mouse (n = 7) gastrocnemius muscle (119‐175 mg tissue) was isolated using a glass on glass homogenizer followed by differential centrifugation. The 800g supernatant from the first centrifugation, containing mito, was divided into two equal volumes. One was exposed to N and the other was not. In each volume, mito were isolated by standard differential centrifugation. State 3 max ADP‐stimulated O 2 consumption rates (J o ) were measured using polarography with malate + pyruvate + glutamate. N increased state 3 J o , 16.1 ± 1.1 vs. 11.9 ± 1.4 nmol O 2 / ml mito suspension / min; P < 0.004, while it decreased protein concentration in the final mito suspension (typically used to adjust final J o values), 1.9 ± 0.1 vs. 2.5 ± 0.1 mg / ml; P < 0.004. Citrate synthase activity in the final mito suspension, indicative of the available mito, was not different in the preparation treated with N vs. that not treated with N (0.067 ± 0.01 vs. 0.065 ± 0.01μmol / min; P = 0.8). These findings suggest that N treatment: 1) hydrolyzes non‐mito contaminating proteins in the final mito pellet, and 2) induces apparent qualitative changes in mito function. Therefore, calculated functional parameters of mito treated with N are not directly comparable to mito not treated with N. Grant Funding Source : Supported by NIH/NIDDK RO1 DK094062

Recent biochemical and cell-based studies identified G0/G1 switch gene 2 (G0S2) as an inhibitor of adipose triglyceride lipase (ATGL), a key mediator of intracellular triacylglycerol (TG) mobilization. Here, we show that upon fasting, G0S2 protein expression exhibits an increase in liver and a decrease in adipose tissue. Global knockout of G0S2 in mice enhanced adipose lipolysis and attenuated gain of body weight and adiposity. More strikingly, G0S2 knockout mice displayed a drastic decrease in hepatic TG content and were resistant to high-fat diet (HFD)-induced liver steatosis, both of which were reproduced by liver-specific G0S2 knockdown. Mice with hepatic G0S2 knockdown also showed increased ketogenesis, accelerated gluconeogenesis, and decelerated glycogenolysis. Conversely, overexpression of G0S2 inhibited fatty acid oxidation in mouse primary hepatocytes and caused sustained steatosis in liver accompanied by deficient TG clearance during the fasting-refeeding transition. In response to HFD, there was a profound increase in hepatic G0S2 expression in the fed state. Global and hepatic ablation of G0S2 both led to improved insulin sensitivity in HFD-fed mice. Our findings implicate a physiological role for G0S2 in the control of adaptive energy response to fasting and as a contributor to obesity-associated liver steatosis.