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In this review, we discuss strengths and limitations of a recent rigorous systematic review and meta-analysis of the literature on associations of all-cause mortality with overweight and obesity. A perspective on its meaning and potential implications are provided. To move this field forward, we suggest modeling BMI as a continuous variable, switching to modeling longevity instead of mortality, and generating large publicly available datasets in broad and diverse populations for discerning the extent to which the BMI–mortality relationship differs between groups and over time. Randomized studies of obesity-related interventions that provide assessments of their actual effects on lifespan or mortality would have great value for helping to establish valid clinical and public health recommendations around weight loss and mortality. [Hide abstract]

The adipocyte-derived hormone, leptin, is a master regulator of energy homeostasis. Leptin action in the central nervous system also contributes to arterial pressure regulation through its capacity to increase renal sympathetic outflow. The accumulating evidence pointing to a key role for leptin in the adverse sympathetic and cardiovascular consequences of excessive adiposity highlight the importance of understanding the mechanisms underlying the sympathetic and cardiovascular effects of leptin. The ability of the leptin receptor to stimulate various intracellular pathways allows leptin to regulate physiological processes in a specific manner. In this review, we examine the role of the PI3K pathway emanating from the leptin receptor in mediating the sympathetic and arterial pressure effects of leptin. We also discuss the relevance of PI3K signaling for obesity-induced hypertension through its role in mediating selective leptin resistance. [Hide abstract]

MicroRNAs (miRNAs) have recently emerged as key regulators of metabolism. However, their potential role in the central regulation of whole-body energy homeostasis is still unknown. In this study we show that the expression of Dicer, an essential endoribonuclease for miRNA maturation, is modulated by nutrient availability and excess in the hypothalamus. Conditional deletion of Dicer in POMC-expressing cells resulted in obesity, characterized by hyperphagia, increased adiposity, hyperleptinemia, defective glucose metabolism and alterations in the pituitary–adrenal axis. The development of the obese phenotype was paralleled by a POMC neuron degenerative process that started around 3 weeks of age. Hypothalamic transcriptomic analysis in presymptomatic POMCDicerKO mice revealed the downregulation of genes implicated in biological pathways associated with classical neurodegenerative disorders, such as MAPK signaling, ubiquitin–proteosome system, autophagy and ribosome biosynthesis. Collectively, our results highlight a key role for miRNAs in POMC neuron survival and the consequent development of neurodegenerative obesity. [Hide abstract]

Structure–function studies have analyzed substitutions within the glucagon-like peptide-1 (GLP-1) sequence that increase resistance to proteolysis, however, the investigation into how such substitutions alter interactions at the GLP-1 receptor (GLP-1R) has captured less attention. This work describes our efforts at identifying relevant interactions between peptide ligands and the GLP-1R extracellular domain that contribute to the positioning of the peptide N-terminus for receptor activation. Alanine substitutions at hydrophilic (Glu127* and Glu128*) and hydrophobic (Leu32*) GLP-1R residues were previously shown to differentially interact with GLP-1 and exendin-4. We examined if these receptor residues influence the activity of GLP-1- and exendin-4-based peptides containing either alanine or glycine at position 2. Additionally, a series of glucagon-based peptides were studied to determine how the central to C-terminal region affects activity. Our results suggest that peptide binding to the GLP-1R is largely driven by hydrophobic interactions with the extracellular domain that orient the N-terminus for activation. [Hide abstract]

Dietary restriction (DR) extends lifespan and promotes metabolic health in evolutionary distinct species. DR is widely believed to promote longevity by causing an energy deficit leading to increased mitochondrial respiration. We here show that inhibitors of mitochondrial complex I promote physical activity, stress resistance as well as lifespan of Caenorhabditis elegans despite normal food uptake, i.e. in the absence of DR. However, complex I inhibition does not further extend lifespan in dietarily restricted nematodes, indicating that impaired complex I activity mimics DR. Promotion of longevity due to complex I inhibition occurs independently of known energy sensors, including DAF-16/FoxO, as well as AAK-2/AMPK and SIR-2.1/sirtuins, or both. Consistent with the concept of mitohormesis, complex I inhibition transiently increases mitochondrial formation of reactive oxygen species (ROS) that activate PMK-1/p38 MAP kinase and SKN-1/NRF-2. Interference with this retrograde redox signal as well as ablation of two redox-sensitive neurons in the head of the worm similarly prevents extension of lifespan. These findings unexpectedly indicate that DR extends organismal lifespan through transient neuronal ROS signaling rather than sensing of energy depletion, providing unexpected pharmacological options to promote exercise capacity and healthspan despite unaltered eating habits. [Hide abstract]

Obesity is at epidemic proportions but treatment options remain limited. Treatment of obesity by calorie restriction (CR) despite having initial success often fails due to rebound weight gain. One possibility is that this reflects an increased body weight (BW) set-point. Indeed, high fat diets (HFD) reduce adult neurogenesis altering hypothalamic neuroarchitecture. However, it is uncertain if these changes are associated with weight rebound or if long-term weight management is associated with reversing this.

Here we show that obese mice have an increased BW set-point and lowering this set-point is associated with rescuing hypothalamic remodelling. Treating obesity by CR using HFD causes weight loss, but not rescued remodelling resulting in rebound weight gain. However, treating obesity by CR using non-HFD causes weight loss, rescued remodelling and attenuates rebound weight gain. We propose that these phenomena may explain why successful short-term weight loss improves obesity in some people but not in others. [Hide abstract]

Restricting energy expenditure is an adaptive response to food shortage. Despite being insulated with massive amount of fat tissues, leptin-deficient mice lose the ability to maintain their body temperature and develop deep hypothermia, which can be suppressed by exogenous leptin, suggesting an important role for leptin in energy expenditure regulation. However, the mechanism underlying the leptin action is not clear. We generated mice with disruption of glutamate release from leptin receptor-expressing neurons by deleting vesicular glutamate transporter 2 in these neurons, and found that these mice developed mild obesity purely due to reduced energy expenditure, exhibited bouts of rapidly reduced energy expenditure, body temperature and locomotion. In addition, these mice exhibited lower energy expenditure and body temperature in response to fasting and were defective in leptin-mediated thermogenic action in brown adipose tissues. Taken together, our results identify a role for glutamate release in mediating leptin action on energy expenditure. [Hide abstract]

The mediobasal hypothalamus (MBH) plays a central role in the regulation of food intake and energy balance. Although the excitatory neurotransmitter glutamate is implicated in energy balance regulation by the MBH, the hypothesis that feeding elicits local glutamate release remains untested. To test this hypothesis, we employed a glutamate biosensor that measures glutamate concentrations at 1-s intervals in conscious, freely behaving rats. Results indicate that feeding is associated with an increase of MBH glutamate concentration that occurs within 1–2 s of oral contact with a food pellet, and the glutamate response to a palatable high-fat pellet is greatly exaggerated relative to chow. In contrast, glutamate responses were not observed during water ingestion or other observed behaviors. These findings indicate that feeding is associated with rapid release of glutamate in the MBH, that this release is exaggerated with an obesogenic food, and that this response is likely stimulated by orosensory factors. [Hide abstract]