Weight Loss and Sleep, Current Evidence in Animal Models and Humans.

Sleep is a vital process essential for survival. The trend of reduction in the time dedicated to sleep has increased in industrialized countries, together with the dramatic increase in the prevalence of obesity and diabetes. Short sleep may increase the risk of obesity, diabetes and cardiovascular disease, and on the other hand, obesity is associated with sleep disorders, such as obstructive apnea disease, insomnia and excessive daytime sleepiness. Sleep and metabolic disorders are linked; therefore, identifying the physiological and molecular pathways involved in sleep regulation and metabolic homeostasis can play a major role in ameliorating the metabolic health of the individual. Approaches aimed at reducing body weight could provide benefits for both cardiometabolic risk and sleep quality, which indirectly, in turn, may determine an amelioration of the cardiometabolic phenotype of individuals. We revised the literature on weight loss and sleep, focusing on the mechanisms and the molecules that may subtend this relationship in humans as in animal models.

Central nicotine induces browning through hypothalamic κ opioid receptor.

Increased body weight is a major factor that interferes with smoking cessation. Nicotine, the main bioactive compound in tobacco, has been demonstrated to have an impact on energy balance, since it affects both feeding and energy expenditure at the central level. Among the central actions of nicotine on body weight, much attention has been focused on its effect on brown adipose tissue (BAT) thermogenesis, though its effect on browning of white adipose tissue (WAT) is unclear. Here, we show that nicotine induces the browning of WAT through a central mechanism and that this effect is dependent on the κ opioid receptor (KOR), specifically in the lateral hypothalamic area (LHA). Consistent with these findings, smokers show higher levels of uncoupling protein 1 (UCP1) expression in WAT, which correlates with smoking status. These data demonstrate that central nicotine-induced modulation of WAT browning may be a target against human obesity.

Metabolic regulation of female puberty via hypothalamic AMPK-kisspeptin signaling.

Conditions of metabolic distress, from malnutrition to obesity, impact, via as yet ill-defined mechanisms, the timing of puberty, whose alterations can hamper later cardiometabolic health and even life expectancy. AMP-activated protein kinase (AMPK), the master cellular energy sensor activated in conditions of energy insufficiency, has a major central role in whole-body energy homeostasis. However, whether brain AMPK metabolically modulates puberty onset remains unknown. We report here that central AMPK interplays with the puberty-activating gene, Kiss1, to control puberty onset. Pubertal subnutrition, which delayed puberty, enhanced hypothalamic pAMPK levels, while activation of brain AMPK in immature female rats substantially deferred puberty. Virogenetic overexpression of a constitutively active form of AMPK, selectively in the hypothalamic arcuate nucleus (ARC), which holds a key population of Kiss1 neurons, partially delayed puberty onset and reduced luteinizing hormone levels. ARC Kiss1 neurons were found to express pAMPK, and activation of AMPK reduced ARC Kiss1 expression. The physiological relevance of this pathway was attested by conditional ablation of the AMPKα1 subunit in Kiss1 cells, which largely prevented the delay in puberty onset caused by chronic subnutrition. Our data demonstrate that hypothalamic AMPK signaling plays a key role in the metabolic control of puberty, acting via a repressive modulation of ARC Kiss1 neurons in conditions of negative energy balance.

Genetic Targeting of GRP78 in the VMH Improves Obesity Independently of Food Intake.

Recent data have demonstrated that the hypothalamic GRP78/BiP (glucose regulated protein 78 kDa/binding immunoglobulin protein) modulates brown adipose tissue (BAT) thermogenesis by acting downstream on AMP-activated protein kinase (AMPK). Herein, we aimed to investigate whether genetic over-expression of GRP78 in the ventromedial nucleus of the hypothalamus (VMH: a key site regulating thermogenesis) could ameliorate very high fat diet (vHFD)-induced obesity. Our data showed that stereotaxic treatment with adenoviruses harboring GRP78 in the VMH reduced hypothalamic endoplasmic reticulum ER stress and reversed vHFD-induced obesity. Herein, we also demonstrated that this body weight decrease was more likely associated with an increased BAT thermogenesis and browning of white adipose tissue (WAT) than to anorexia. Overall, these results indicate that the modulation of GRP78 in the VMH may be a target against obesity.

Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK.

Estrogens play a major role in the modulation of energy balance through central and peripheral actions. Here, we demonstrate that central action of estradiol (E2) inhibits AMP-activated protein kinase (AMPK) through estrogen receptor alpha (ERα) selectively in the ventromedial nucleus of the hypothalamus (VMH), leading to activation of thermogenesis in brown adipose tissue (BAT) through the sympathetic nervous system (SNS) in a feeding-independent manner. Genetic activation of AMPK in the VMH prevented E2-induced increase in BAT-mediated thermogenesis and weight loss. Notably, fluctuations in E2 levels during estrous cycle also modulate this integrated physiological network. Together, these findings demonstrate that E2 regulation of the VMH AMPK-SNS-BAT axis is an important determinant of energy balance and suggest that dysregulation in this axis may account for the common changes in energy homeostasis and obesity linked to dysfunction of the female gonadal axis.

Hypothalamic mTOR pathway mediates thyroid hormone-induced hyperphagia in hyperthyroidism.

Hyperthyroidism is characterized in rats by increased energy expenditure and marked hyperphagia. Alterations of thermogenesis linked to hyperthyroidism are associated with dysregulation of hypothalamic AMPK and fatty acid metabolism; however, the central mechanisms mediating hyperthyroidism-induced hyperphagia remain largely unclear. Here, we demonstrate that hyperthyroid rats exhibit marked up-regulation of the hypothalamic mammalian target of rapamycin (mTOR) signalling pathway associated with increased mRNA levels of agouti-related protein (AgRP) and neuropeptide Y (NPY), and decreased mRNA levels of pro-opiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC), an area where mTOR co-localizes with thyroid hormone receptor-α (TRα). Central administration of thyroid hormone (T3) or genetic activation of thyroid hormone signalling in the ARC recapitulated hyperthyroidism effects on feeding and the mTOR pathway. In turn, central inhibition of mTOR signalling with rapamycin in hyperthyroid rats reversed hyperphagia and normalized the expression of ARC-derived neuropeptides, resulting in substantial body weight loss. The data indicate that in the hyperthyroid state, increased feeding is associated with thyroid hormone-induced up-regulation of mTOR signalling. Furthermore, our findings that different neuronal modulations influence food intake and energy expenditure in hyperthyroidism pave the way for a more rational design of specific and selective therapeutic compounds aimed at reversing the metabolic consequences of this disease.

A novel phenotypic expression associated with a new mutation in LMNA gene, characterized by partial lipodystrophy, insulin resistance, aortic stenosis and hypertrophic cardiomyopathy.

BACKGROUND: Lipodystrophies are a heterogeneous group of diseases characterized by abnormal fat distribution. Familial partial lipodystrophy 2 (FPLD2) is due to mutations in the LMNA gene. Previous studies have suggested that LMNA mutations 5' to the nuclear localization signal (NLS) are more likely to underlie laminopathies with cardiac or skeletal muscle involvement, while mutations 3' to the NLS are more likely to underlie lipodystrophy and progeroid syndromes. OBJECTIVE: To study the clinical and molecular features of a subject with FPLD. SUBJECTS AND METHODS: We carried out mutational analysis of LMNA gene in a woman with FPLD phenotype and in her relatives. Insulin resistance was evaluated by minimal model. Body composition was evaluated by dual-energy X-ray absorptiometry (DEXA). Echocardiography was done in affected subjects. 3T3-L1 preadipocytes were transfected with wild-type or mutant prelamin A constructs. In transfected cells, lamin A was detected using a Cy3-conjugated monoclonal anti-FLAG antibody. RESULTS: The patient showed atypical fat distribution, insulin resistance, severe aortic stenosis and hypertrophic cardiomyopathy. She has an affected 11-year-old son, not yet lipodystrophic but with an incipient aortic disease. LMNA sequencing showed that mother and son were both heterozygous for a novel c.1772G > T missense mutation in exon 11, which causes the substitution of the cysteine at residue 591 by a phenylalanine (C591F). In mouse preadipocytes transfected with the mutant human LMNA gene, the mutant lamin A isoform was mislocated in the nucleus. CONCLUSIONS: This patient shows a novel clinical form of FPLD2, due to a mutation affecting lamin A only, with cardiac involvement.