The essential role of the brain in maintaining energy homeostasis has motivated the drive to define the neural circuitry that integrates external and internal stimuli to enact appropriate and ...consequential metabolic and behavioral responses. The hypothalamus has received significant attention in this regard given its ability to influence feeding behavior, yet organisms rely on a much broader diversity and distribution of neuronal networks to regulate both energy intake and expenditure. Because energy balance is a fundamental determinant of survival and success of an organism, it is not surprising that emerging data connect circuits controlling feeding and energy balance with higher brain functions and degenerative processes. In this review, we will highlight both classically defined and emerging aspects of brain control of energy homeostasis.
In this Review Article, Waterson and Horvath highlight classically defined (such as the hypothalamus) and emerging aspects of brain control of energy homeostasis and how disruption of the underlying pathways may play a role in both metabolic and psychiatric disease.
Generation, transformation, and utilization of organic molecules in support of cellular differentiation, growth, and maintenance are basic tenets that define life. In eukaryotes, mitochondrial oxygen ...consumption plays a central role in these processes. During the process of oxidative phosphorylation, mitochondria utilize oxygen to generate ATP from organic fuel molecules but in the process also produce reactive oxygen species (ROS). While ROS have long been appreciated for their damage-promoting, detrimental effects, there is now a greater understanding of their roles as signaling molecules. Here, we review mitochondrial ROS-mediated signaling pathways with an emphasis on how they are involved in various basal and adaptive physiological responses that control organismal homeostasis.
This Review takes a finer look at how mitochondrial oxygen, while deleterious in some contexts, plays a key role in supporting the processes that control physiology.
Mitochondria are key organelles in the maintenance of cellular energy metabolism and integrity. Here, we show that mitochondria number decrease but their size increase in orexigenic agouti-related ...protein (Agrp) neurons during the transition from fasted to fed to overfed state. These fusion-like dynamic changes were cell-type specific, as they occurred in the opposite direction in anorexigenic pro-opiomelanocortin (POMC) neurons. Interfering with mitochondrial fusion mechanisms in Agrp neurons by cell-selectively knocking down mitofusin 1 (Mfn1) or mitofusin 2 (Mfn2) resulted in altered mitochondria size and density in these cells. Deficiency in mitofusins impaired the electric activity of Agrp neurons during high-fat diet (HFD), an event reversed by cell-selective administration of ATP. Agrp-specific Mfn1 or Mfn2 knockout mice gained less weight when fed a HFD due to decreased fat mass. Overall, our data unmask an important role for mitochondrial dynamics governed by Mfn1 and Mfn2 in Agrp neurons in central regulation of whole-body energy metabolism.
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•Mitochondria dynamics in Agrp neurons is regulated by metabolic status•Mitochondria fusion in Agrp neurons during HFD is dependent on Mfn1 and Mfn2•Impaired fusion alters the electrical activity of Agrp neurons during HFD•Mfn1 or Mfn2 knockout in Agrp neurons protect mice against DIO
The link between cellular metabolism and whole-body energy balance remains enigmatic with changes in feeding often leading to changes in mitochondrial dynamics. Remarkably, perturbation of mitochondrial fusion mechanisms in AGRP neurons, cells that regulate feeding, results in systemic changes in whole-body energy metabolism.
The powerful regulation of bone mass exerted by the brain suggests the existence of bone-derived signals modulating this regulation or other functions of the brain. We show here that the ...osteoblast-derived hormone osteocalcin crosses the blood-brain barrier, binds to neurons of the brainstem, midbrain, and hippocampus, enhances the synthesis of monoamine neurotransmitters, inhibits GABA synthesis, prevents anxiety and depression, and favors learning and memory independently of its metabolic functions. In addition to these postnatal functions, maternal osteocalcin crosses the placenta during pregnancy and prevents neuronal apoptosis before embryos synthesize this hormone. As a result, the severity of the neuroanatomical defects and learning and memory deficits of Osteocalcin−/− mice is determined by the maternal genotype, and delivering osteocalcin to pregnant Osteocalcin−/− mothers rescues these abnormalities in their Osteocalcin−/− progeny. This study reveals that the skeleton via osteocalcin influences cognition and contributes to the maternal influence on fetal brain development.
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•Osteocalcin signals in the brain and favors postnatal neurogenesis•Osteocalcin prevents anxiety and depression and favors memory•Maternal osteocalcin crosses the placenta and favors fetal brain development•Maternal osteocalcin influences spatial learning and memory in adult offspring
Osteocalcin is a hormone produced in the skeleton that is able to traverse the blood-brain barrier to regulate brain development and adult neurogenesis as well as control complex behaviors.
Mitochondria play a central role in the regulation of energy metabolism in oocytes and preimplantation embryos, where the number and morphology of mitochondria and mitochondrial DNA (mtDNA) content ...are tightly regulated. A number of mouse models with mitochondrial dysfunction result in infertility, further confirming the key role of mitochondria in female reproductive function. When cells and organisms detect mitochondrial dysfunction they use response mechanisms directed at recovering salvageable mitochondria and eliminating mitochondria that can no longer be rescued. Among these mechanisms, mitochondrial unfolded protein response (UPRmt) has recently been linked with prevention of aging, as compromised mitochondrial stress response contributes to age-related accumulation of damaged proteins, reduced oxidative phosphorylation, and increased reactive oxygen species (ROS) production. These mechanisms seem to be especially relevant for reproduction, as targeted deletion of the UPRmt–regulatory gene Clpp results in female infertility, with impaired oocyte maturation and two-cell embryo development, and failure to form blastocysts. In addition, absence of CLPP results in accelerated depletion of follicles, and a phenotype similar to premature reproductive aging. Further studies will provide novel mechanistic insights for physiologic and pathologic control of oocyte and early embryonic mitochondrial function, which can be exploited for the development of novel therapeutic approaches for the promotion of fertility during the aging process.
Mitofusin 2 (MFN2) plays critical roles in both mitochondrial fusion and the establishment of mitochondria-endoplasmic reticulum (ER) interactions. Hypothalamic ER stress has emerged as a causative ...factor for the development of leptin resistance, but the underlying mechanisms are largely unknown. Here, we show that mitochondria-ER contacts in anorexigenic pro-opiomelanocortin (POMC) neurons in the hypothalamus are decreased in diet-induced obesity. POMC-specific ablation of Mfn2 resulted in loss of mitochondria-ER contacts, defective POMC processing, ER stress-induced leptin resistance, hyperphagia, reduced energy expenditure, and obesity. Pharmacological relieve of hypothalamic ER stress reversed these metabolic alterations. Our data establish MFN2 in POMC neurons as an essential regulator of systemic energy balance by fine-tuning the mitochondrial-ER axis homeostasis and function. This previously unrecognized role for MFN2 argues for a crucial involvement in mediating ER stress-induced leptin resistance.
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•POMC neuron mitochondrial dynamics and ER interactions are altered in DIO mice•Mfn2-deleted POMC neuron mice are obese due to ER stress-induced leptin resistance•Mfn2 deficiency in POMC neurons leads to reduced α-MSH production•Central relieve of ER stress rescues the phenotype caused by Mfn2 deletion
Diet-induced obesity is associated with systemic changes, including the induction of ER stress in the hypothalmus. These changes may be explained by a loss of mitochondria-ER contacts caused by perturbation of mitofusin 2 function in a specific subset of neurons that ultimately leads to ER stress-induced leptin resistance and obesity.
Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake, but druggable biochemical pathways that control this response remain elusive. Thus, genetic ...ablation of insulin or leptin signaling in AgRP neurons is predicted to reduce satiety but fails to do so. FoxO1 is a shared mediator of both pathways, and its inhibition is required to induce satiety. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G-protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, whereas Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity.
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► FoxO1 knockout in AgRP neurons mimics insulin and leptin action ► FoxO1-deficient AgRP mice are lean and have reduced food intake ► Gpr17 is a FoxO1 target, and its expression promotes food intake ► Agonists of Gpr17 increase food intake, whereas antagonists curtail it
AgRP neurons respond to leptin and insulin, regulating food intake via FoxO1 signaling. Antagonists of a newly identified FoxO1 target, GPR17, promote satiety in mice, which suggests that this pathway can be targeted to treat obesity.
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•Development of AD disease-modifying therapies are futile thus far.•Research efforts for effective AD therapy broaden targets and treatment options.•Current biomarkers are not ...reliable predictors of effectiveness of new treatments.•Advanced functional brain assessment tools can increase success in clinical trials.
The development of the next generation therapy for Alzheimer’s disease (AD) presents a huge challenge given the number of promising treatment candidates that failed in trials, despite recent advancements in understanding of genetic, pathophysiologic and clinical characteristics of the disease. This review reflects some of the most current concepts and controversies in developing disease-modifying and new symptomatic treatments. It elaborates on recent changes in the AD research strategy for broadening drug targets, and potentials of emerging non-pharmacological treatment interventions. Established and novel biomarkers are discussed, including emerging cerebrospinal fluid and plasma biomarkers reflecting tau pathology, neuroinflammation and neurodegeneration. These fluid biomarkers together with neuroimaging findings can provide innovative objective assessments of subtle changes in brain reflecting disease progression. A particular emphasis is given to neurophysiological biomarkers which are well-suited for evaluating the brain overall neural network integrity and function. Combination of multiple biomarkers, including target engagement and outcome biomarkers will empower translational studies and facilitate successful development of effective therapies.
Nutrient availability is critical for the physiological functions of all tissues. By contrast, an excess of nutrients such as carbohydrate and fats impair health and shorten life due by stimulating ...chronic diseases, including diabetes, cancer and neurodegeneration. The control of circulating glucose and lipid levels involve mitochondria in both central and peripheral mechanisms of metabolism regulation. Mitochondrial uncoupling protein 2 (UCP2) has been implicated in physiological and pathological processes related to glucose and lipid metabolism, and in this review we discuss the latest data on the relationships between UCP2 and glucose and lipid sensing from the perspective of specific hypothalamic neuronal circuits and peripheral tissue functions. The goal is to provide a framework for discussion of future therapeutic strategies for metabolism-related chronic diseases.
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