A potential link between muscle peroxisome proliferator- activated receptor-alpha signaling and obesity-related diabetes.

The role of the peroxisome proliferator-activated receptor-alpha (PPARalpha) in the development of insulin-resistant diabetes was evaluated using gain- and loss-of-function approaches. Transgenic mice overexpressing PPARalpha in muscle (MCK-PPARalpha mice) developed glucose intolerance despite being protected from diet-induced obesity. Conversely, PPARalpha null mice were protected from diet-induced insulin resistance in the context of obesity. In skeletal muscle, MCK-PPARalpha mice exhibited increased fatty acid oxidation rates, diminished AMP-activated protein kinase activity, and reduced insulin-stimulated glucose uptake without alterations in the phosphorylation status of key insulin-signaling proteins. These effects on muscle glucose uptake involved transcriptional repression of the GLUT4 gene. Pharmacologic inhibition of fatty acid oxidation or mitochondrial respiratory coupling prevented the effects of PPARalpha on GLUT4 expression and glucose homeostasis. These results identify PPARalpha-driven alterations in muscle fatty acid oxidation and energetics as a potential link between obesity and the development of glucose intolerance and insulin resistance.

Neural correlates of clinical improvement in response to N-acetylcysteine in adolescents with non-suicidal self-injury.

Non-suicidal self-injury (NSSI) is a serious clinical problem that is common in adolescents. Novel, biologically-informed approaches for treating NSSI in adolescents are needed to prevent negative outcomes such as chronic NSSI and future suicide attempts. N-acetylcysteine (NAC) has been used successfully to address other conditions that involve repetitive maladaptive behaviors and may have utility in addressing NSSI. This study explored neural circuit changes following an open-label, 8-week trial of NAC in female adolescents with NSSI. We measured whole-brain resting-state functional connectivity (RSFC) of the amygdala and the nucleus accumbens before and after treatment using resting-state functional neuroimaging. Usable neuroimaging data from both pre- and post-treatment were available for 18 participants. Reduction in NSSI frequency was associated with a decrease in left amygdala RSFC with right supplementary motor area (SMA), but with an increase in right amygdala RSFC with right inferior frontal cortex. For nucleus accumbens, a reduction in NSSI frequency was associated with a decrease in connectivity between right nucleus accumbens and left superior medial frontal cortex. We also report change in similar circuits accompanying clinical improvement in depression and global psychopathology measures. These preliminary findings suggest amygdala and nucleus accumbens-based circuits as potential treatment targets, and set the stage for future research designed to confirm these neural targets using randomized, placebo-controlled designs to confirm clinical efficacy and mechanisms of effect.

Brain activation in response to overt and covert fear and happy faces in women with borderline personality disorder.

Borderline personality disorder (BPD) is a serious condition involving emotion dysregulation. Past research has identified BPD-associated differences within fronto-limbic circuitry during conditions of processing negative emotion. Functional magnetic resonance imaging (fMRI) paradigms that incorporate overt and covert (masked) presentations of emotional stimuli can provide complementary information about neural systems underlying emotion processing (e.g., both slow [overt] and fast [covert; automatic] processing pathways). This study examined brain activation during processing of overt and covert presentations of emotional faces in 12 women with BPD and 12 age-matched healthy controls. To assess a range of emotional valence and arousal, we examined responses to fear, happy and neutral expressions. All participants underwent an fMRI scanning session in which participants passively viewed emotional faces. Scanning sessions consisted of 5 runs including: (1) Overt Fear (OF) versus Neutral (N), (2) Covert Fear (CF) versus Covert Neutral (CN), (3) Overt Happy (OH) versus N, (4) Covert Happy (CH) versus CN, and (5) N versus fixation. We compared whole-brain activation between groups for each run. In response to overt fear, BPD patients showed greater activation both in left amygdala and in several frontal cortical regions. There were no significant differences in brain activation in response to overt happy faces. In response to covert fear and covert happy stimuli, the BPD group also showed greater activation than controls in several regions including frontal and temporal cortical regions, as well as cerebellum and thalamus. These findings add to prior reports suggesting increased amygdala activation in BPD, but we found this only in the overt fear versus fixation condition. In this sample, BPD patients showed hyper-activation, rather than hypo-activation, of cortical regulatory regions during overt fear. Enhanced cortical recruitment in response to covert fear and happy faces in BPD could reflect a more extended response system in which stimuli that typically only activate automatic pathways are additionally tapping into cortical regulatory systems. The observation of this pattern both in response to fear and in response to happy presentations suggests that the effect of arousal may be as or more impactful than the effect of emotional valence.

An adolescent with nonsuicidal self-injury: a case and discussion of neurobiological research on emotion regulation.

The management of nonsuicidal self-injurious behavior is a common focus of clinical care, particularly in the treatment of adolescents and young adults. Increased recognition of this problem has led to proposed criteria for future study in DSM-5, which may be beneficial in advancing the field. Clinical care may be fruitfully informed by an understanding of the neurodevelopmental underpinnings of this behavior. The authors discuss the current status of neurobiological research related to nonsuicidal self-injury with a focus on the key dimension of emotion regulation. A case is presented to illustrate the critical points. Preliminary empirical evidence suggests disturbances in neurobiological systems relevant to emotion regulation. Disturbances involve engagement of limbic brain regions and frontal regulatory brain regions that may evolve over time. Additionally, disturbances are observed in serotonin and physiological response systems relevant to emotion regulation. Treatment with serotonin reuptake inhibitors may be most beneficial in combination with dialectical behavioral therapy to address safety, build self-soothing strategies to enhance emotion regulation, and reduce interpersonal sensitivity. Delineation of the neurobiological markers that reflect successful treatment response will help in the identification of new avenues for research and the development of personalized treatments for adolescents with nonsuicidal self-injury.

Hepatic lipin 1beta expression is diminished in insulin-resistant obese subjects and is reactivated by marked weight loss.

OBJECTIVE: Lipin 1 plays critical roles in controlling energy metabolism. We sought to determine the expression of lipin 1 isoforms (lipin 1alpha and -beta) in liver and adipose tissue of obese subjects and to evaluate cellular mechanisms involved in the regulation of lipin 1 expression by physiologic stimuli. RESEARCH DESIGN AND METHODS: The expression of lipin 1alpha and -beta was quantified in liver and adipose tissue of extremely obese (average BMI 60.8 kg/m(2)) human subjects undergoing gastric bypass surgery (GBS). Second, the expression of lipin 1 was evaluated in HepG2 cells in response to overexpression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha under normal or hyperinsulinemic conditions. RESULTS: The expression of lipin 1beta in liver and adipose tissue was inversely related to BMI, fasting plasma insulin concentration, and the homeostasis model assessment of insulin resistance but was significantly increased by marked weight loss and insulin sensitization following GBS. Hepatic lipin 1beta mRNA levels were strongly correlated with the expression of PGC-1alpha, and overexpression of PGC-1alpha in HepG2 cells increased lipin 1 expression. Conversely, hyperinsulinemic culture conditions downregulated the expression of lipin 1beta, PGC-1alpha, and their known target genes involved in mitochondrial metabolism in HepG2 cells. Finally, overexpression of lipin 1beta or PGC-1alpha reversed the effect of hyperinsulinemia on the expression of their target genes. CONCLUSIONS: These studies suggest that hepatic lipin 1beta and PGC-1alpha expression are downregulated by obesity and obesity-related metabolic perturbations in human subjects, likely due to alterations in insulin concentration or sensitivity.