Depression and metabolism: linking changes in leptin and ghrelin to mood

Major depressive disorder is associated with an elevated risk of numerous metabolic disturbances, including obesity, metabolic syndrome, insulin-dependent diabetes mellitus type II, and death after myocardial infarction. Several recent papers also indicate that disturbances of mood may alter peripheral signaling pathways that regulate metabolic processes, including those involving leptin and ghrelin

Obesity : an evolutionary context

This work was supported by the Shenzhen Key Laboratory of Metabolic Health (ZDSYS20210427152400001) to JRS and by the US National Institutes of Health grants R01DK100659, R01DK118725, P01DK119130 and R01DK12724 to JKE.Peer reviewedPublisher PD

The Need to Feed Homeostatic and Hedonic Control of Eating

AbstractFeeding provides substrate for energy metabolism, which is vital to the survival of every living animal and therefore is subject to intense regulation by brain homeostatic and hedonic systems. Over the last decade, our understanding of the circuits and molecules involved in this process has changed dramatically, in large part due to the availability of animal models with genetic lesions. In this review, we examine the role played in homeostatic regulation of feeding by systemic mediators such as leptin and ghrelin, which act on brain systems utilizing neuropeptide Y, agouti-related peptide, melanocortins, orexins, and melanin concentrating hormone, among other mediators. We also examine the mechanisms for taste and reward systems that provide food with its intrinsically reinforcing properties and explore the links between the homeostatic and hedonic systems that ensure intake of adequate nutrition

Serotonergic Control of Metabolic Homeostasis

New treatments are urgently needed to address the current epidemic of obesity and diabetes. Recent studies have highlighted multiple pathways whereby serotonin (5-HT) modulates energy homeostasis, leading to a renewed interest in the identification of 5-HT-based therapies for metabolic disease. This review aims to synthesize pharmacological and genetic studies that have found diverse functions of both central and peripheral 5-HT in the control of food intake, thermogenesis, and glucose and lipid metabolism. We also discuss the potential benefits of targeting the 5-HT system to combat metabolic disease

Melanocortin 4 Receptors Reciprocally Regulate Sympathetic and Parasympathetic Preganglionic Neurons

Melanocortin 4 receptors (MC4Rs) in the central nervous system are key regulators of energy and glucose homeostasis. Notably, obese patients with MC4R mutations are hyperinsulinemic and resistant to obesity-induced hypertension. Although these effects are likely dependent upon the activity of the autonomic nervous system, the cellular effects of MC4Rs on parasympathetic and sympathetic neurons remain undefined. Here, we show that MC4R agonists inhibit parasympathetic preganglionic neurons in the brainstem. In contrast, MC4R agonists activate sympathetic preganglionic neurons in the spinal cord. Deletion of MC4Rs in cholinergic neurons resulted in elevated levels of insulin. Furthermore, re-expression of MC4Rs specifically in cholinergic neurons (including sympathetic preganglionic neurons) restores obesity-associated hypertension in MC4R null mice. These findings provide a cellular correlate of the autonomic side effects associated with MC4R agonists and demonstrate a role for MC4Rs expressed in cholinergic neurons in the regulation of insulin levels and in the development of obesity-induced hypertension

Appropriate Inhibition of Orexigenic Hypothalamic Arcuate Nucleus Neurons Independently of Leptin Receptor/STAT3 Signaling

Leptin directly suppresses the activity of orexigenic neurons in the hypothalamic arcuate nucleus (ARC). We examined c-Fos-like immunoreactivity (CFLIR) as a marker of ARC neuronal activity in db/db mice devoid of the signaling form of the leptin receptor (LRb) and s/s mice that express LRbS1138 [which is defective for STAT3 (signal transducer and activator of transcription) signaling]. Both db/db and s/s animals are hyperphagic and obese. This analysis revealed that CFLIR in agouti related peptide-expressing orexigenic ARC neurons is basally elevated in db/db but not s/s mice. Consistent with these observations, electrophysiologic evaluation of a small number of neurons in s/s animals suggested that leptin appropriately suppresses the frequency of IPSCs on ARC proopiomelanocortin (POMC) neurons that are mediated by the release of GABA from orexigenic ARC neurons. CFLIR in POMC neurons of s/s mice was also increased compared with db/db animals. Thus, these data suggest that, although LRb→STAT3 signaling is crucial for the regulation of feeding, it is not required for the acute or chronic regulation of orexigenic ARC neurons, and the activation of STAT3-mediated transcription by leptin is not required for the appropriate development of leptin responsiveness in these neurons

A Cardiac MicroRNA Governs Systemic Energy Homeostasis by Regulation of MED13

SummaryObesity, type 2 diabetes, and heart failure are associated with aberrant cardiac metabolism. We show that the heart regulates systemic energy homeostasis via MED13, a subunit of the Mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors. MED13, in turn, is negatively regulated by a heart-specific microRNA, miR-208a. Cardiac-specific overexpression of MED13 or pharmacologic inhibition of miR-208a in mice confers resistance to high-fat diet-induced obesity and improves systemic insulin sensitivity and glucose tolerance. Conversely, genetic deletion of MED13 specifically in cardiomyocytes enhances obesity in response to high-fat diet and exacerbates metabolic syndrome. The metabolic actions of MED13 result from increased energy expenditure and regulation of numerous genes involved in energy balance in the heart. These findings reveal a role of the heart in systemic metabolic control and point to MED13 and miR-208a as potential therapeutic targets for metabolic disorders.PaperCli

Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice

Obesity is closely associated with the metabolic syndrome, a combination of disorders including insulin resistance, diabetes, dyslipidemia, and hypertension. A role for local glucocorticoid reamplification in obesity and the metabolic syndrome has been suggested. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active cortisol from inactive 11-keto forms, and aP2-HSD1 mice with relative transgenic overexpression of this enzyme in fat cells develop visceral obesity with insulin resistance and dyslipidemia. Here we report that aP2-HSD1 mice also have high arterial blood pressure (BP). The mice have increased sensitivity to dietary salt and increased plasma levels of angiotensinogen, angiotensin II, and aldosterone. This hypertension is abolished by selective angiotensin II receptor AT-1 antagonist at a low dose that does not affect BP in non-Tg littermates. These findings suggest that activation of the circulating renin-angiotensin system (RAS) develops in aP2-HSD1 mice. The long-term hypertension is further reflected by an appreciable hypertrophy and hyperplasia of the distal tubule epithelium of the nephron, resembling salt-sensitive or angiotensin II–mediated hypertension. Taken together, our findings suggest that overexpression of 11β-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS. The potential role of adipose 11β-HSD1 in mediating critical features of the metabolic syndrome extends beyond obesity and metabolic complications to include the most central cardiovascular feature of this disorder

PTP1B Regulates Leptin Signal Transduction In Vivo

AbstractMice lacking the protein-tyrosine phosphatase PTP1B are hypersensitive to insulin and resistant to obesity. However, the molecular basis for resistance to obesity has been unclear. Here we show that PTP1B regulates leptin signaling. In transfection studies, PTP1B dephosphorylates the leptin receptor-associated kinase, Jak2. PTP1B is expressed in hypothalamic regions harboring leptin-responsive neurons. Compared to wild-type littermates, PTP1B−/− mice have decreased leptin/body fat ratios, leptin hypersensitivity, and enhanced leptin-induced hypothalamic Stat3 tyrosyl phosphorylation. Gold thioglucose treatment, which ablates leptin-responsive hypothalamic neurons, partially overcomes resistance to obesity in PTP1B−/− mice. Our data indicate that PTP1B regulates leptin signaling in vivo, likely by targeting Jak2. PTP1B may be a novel target to treat leptin resistance in obesity

A role for ΔfosB in calorie restriction-induced metabolic changes

Background: Calorie restriction (CR) induces long-term changes in motivation to eat highly palatable food and, in body weight regulation, through an unknown mechanism. Methods: After a period of CR and refeeding, mice were assessed by behavioral and metabolic studies and for levels of the transcription factor ΔFosB. The ΔFosB levels were then increased specifically in nucleus accumbens (NAc) with viral-mediated gene transfer, and behavioral and metabolic studies were conducted. Results: We show that accumulation of ΔFosB in the NAc shell after CR in mice corresponds to a period of increased motivation for high fat reward and reduced energy expenditure. Furthermore, ΔFosB overexpression in this region increases instrumental responding for a high fat reward via an orexin-dependent mechanism while also decreasing energy expenditure and promoting adiposity. Conclusions: These results suggest that ΔFosB signaling in NAc mediates adaptive responses to CR.Instituto Multidisciplinario de Biología Celula