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T3 and Triac inhibit leptin secretion and expression in brown and white rat adipocytes.

Leptin regulates appetite, inhibits food intake, and seems to increase energy expenditure. We investigated the effect of triiodothyroacetic acid (Triac), a metabolite of T3, which seems to be more thermogenic than T3, on leptin secretion and mRNA expression. Rat primary cultures of white and brown adipocytes were treated with increasing concentrations of Triac and T3. The effect of different types of serum and insulin concentrations was also tested. Serum inhibited leptin secretion and mRNA expression. Leptin secretion was also clearly inhibited by Triac and T3 in a dose-dependent manner and with similar potency. In the presence of norepinephrine (NE), Triac and T3 had a similar inhibitory effect, but the inhibition was almost complete in white adipocytes. Parallel results were found at the mRNA level, where Triac and T3 had similar inhibitory potency, both alone and with NE. We also show that insulin induced dose- and time-dependent increases in leptin secretion, reaching maximum levels at 0.5 and 3 nM insulin for white and brown adipocytes, respectively. Leptin secretion was higher in white than in brown adipocytes. The increases in leptin secretion were preceded by increases in leptin mRNA. In conclusion, these data demonstrate for the first time that Triac, like T3 and serum, inhibits leptin secretion and expression in white and brown adipocytes, whereas insulin has the opposite effect.

Adipocytes↗

The effect of REM sleep deprivation on motivation for food reward.

Prolonged sleep deprivation in rats produces a characteristic syndrome consisting of an increase in food intake yet a decrease in weight. Moreover, the increase in food intake generally precedes the weight loss, suggesting that sleep deprivation may affect appetitive behaviors. Using the multiple platform method to produce rapid eye movement (REM) sleep deprivation, we investigated the effect of REM sleep deprivation (REMSD) on motivation for food reward utilizing food-reinforced operant tasks. In acquisition or maintenance of an operant task, REM sleep-deprived rats, with or without simultaneous food restriction, decreased responding for sucrose pellet reward in comparison to controls, despite the fact that all REM sleep-deprived rats lost weight. Furthermore, the overall response deficit of the REM sleep-deprived rats was due to a within-session decline in responding. REM sleep-deprived rats showed evidence of understanding the contingency of the task comparable to controls throughout deprivation period, suggesting that the decrements in responding were not primarily related to deficits in learning or memory. Rather, REM sleep deprivation appears to alter systems involved in motivational processes, reward, and/or attention.

Animals↗

Differential hypothalamic neuronal activation following peripheral injection of GLP-1 and oxyntomodulin in mice detected by manganese-enhanced magnetic resonance imaging.

The anorexigenic gut hormones oxyntomodulin (OXM) and glucagon-like peptide-1 (GLP-1) are thought to physiologically regulate appetite and food intake. Using manganese-enhanced magnetic resonance imaging, we have shown distinct patterns of neuronal activation in the hypothalamus in response to intraperitoneal injections into fasted mice of 900 and 5400 nmol/kg OXM or 900 nmol/kg GLP-1. Administration of OXM at either dose resulted in a reduced rate of signal enhancement, reflecting a reduction in neuronal activity, in the arcuate, paraventricular, and supraoptic nuclei of the hypothalamus. Conversely, GLP-1 caused a reduction in signal enhancement in the paraventricular nucleus only and an increase in the ventromedial hypothalamic nucleus. Our data show that these two apparently similar peptides generate distinct patterns of activation within the hypothalamus, suggesting that GLP-1 and OXM may act via different hypothalamic pathways.

Animals↗

The melanocortins and melanin-concentrating hormone in the central regulation of feeding behavior and energy homeostasis.

A number of different neuropeptides exert powerful concerted controls on feeding behavior and energy balance, most of them being produced in hypothalamic neuronal networks under stimulation by anabolic and catabolic peripheral hormones such as ghrelin and leptin, respectively. These peptide-expressing neurons interconnect extensively to integrate the multiple opposing signals that mediate changes in energy expenditure. In the present review I have summarized our current knowledge about two key peptidic systems involved in regulating appetite and energy homeostasis, the melanocortin system (alpha-MSH, agouti and Agouti-related peptides, MC receptors and mahogany protein) and the melanin-concentrating hormone system (proMCH-derived peptides and MCH receptors) that contribute to satiety and feeding-initiation, respectively, with concurrent effects on energy expenditure. I have focused particularly on recent data concerning transgenic mice and the ongoing development of MC/MCH receptor antagonists/agonists that may represent promising drugs to treat human eating disorders on both sides of the energy balance (anorexia, obesity).

Agouti Signaling Protein↗

Management of overweight and obesity in adults: behavioral intervention for long-term weight loss and maintenance.

BACKGROUND: The World Health Organization has identified obesity as a global epidemic. While weight loss is a considerable challenge, long-term maintenance of weight loss is an even greater problem. AIMS: This review of the assessment and management of overweight and obesity in adults covers factors contributing to overweight and obesity, components of weight-loss management, and interventions and effects of behavioral treatment for long-term weight loss and maintenance. METHODS: A thorough search of the medical and nursing literature recorded in the MEDLINE database from 1995 to 2003 was conducted by using the keywords "overweight", "obesity", and "behavioral therapy". RESULTS: Obesity is a complex, multifaceted condition in which excessive body fat places a person at risk of multiple health problems. Excessive body fat results from energy intake that exceeds energy expenditure. CONCLUSIONS: Increasing evidence suggests that obesity is not simply a problem of will power or self-control but a complex disorder involving appetite regulation and energy metabolism that is associated with a variety of comorbid conditions. Effective strategies of weight loss require management strategies in a combined approach of dietary therapy and physical activity by using behavioral interventions.

Adult↗

The relation of serum and follicular fluid leptin and ovarian steroid levels in response to induction of ovulation in in vitro fertilization cycles.

OBJECTIVE: Leptin restores energy homeostasis and regulates appetite and body weight by communicating the energy status to the central nervous system. Although there is strong evidence that leptin affects reproduction, its role in the control of reproductive physiology is little understood. STUDY DESIGN: We studied leptin concentrations in the serum and follicular fluid of 65 women undergoing ovarian hyperstimulation for in vitro fertilization (IVF). Fasting serum samples were collected (1) on the 3rd day of the cycle before IVF and (2) at the time of oocyte retrieval. Serum concentrations of leptin, estradiol (E2), progesterone, FSH, LH, prolactin, total testosterone, DHEA-SO4, and TSH and follicular fluid concentrations of leptin, E2, and progesterone were measured. RESULTS: Serum leptin values increased on average by 66.4% over basal leptin levels on the day of oocyte pick-up (OPU). A positive correlation between leptin increase and body mass index was observed. The serum leptin level was similar to that in follicular fluid o the day of OPU. E2 levels increased 34.5-fold with controlled ovarian hyperstimulation. There was a negative correlation between the increase in leptin levels and in E2 levels (P <0.05) and in the number of oocytes harvested (P <0.05). CONCLUSION: The significant increase in serum leptin levels during controlled ovarian hyperstimulation indicates a possible role of leptin in reproductive function. The increase in leptin levels is negatively correlated with ovarian response evaluated by E2 production and number of oocytes retrieved. This might be due to the reduced ovarian response through negative feedback of leptin to the ovaries at high levels.

Adult↗

Leptin and its soluble receptor in plasma of patients suffering from remitting-relapsing multiple sclerosis (MS) In vitro effects of leptin on type-1 and type-2 cytokine secretion by peripheral blood mononuclear cells, T-cells and monocytes of MS patients.

Leptin is synthesized by adipocytes to regulate appetite. Leptin has also been implicated in the pathogenesis of multiple sclerosis (MS) leading to speculation about a beneficial effect of fasting to autoimmune patients. We measured plasma leptin and its soluble receptor (OB-Rs) in 52 MS patients and 50 controls. We also cultured MS and control peripheral blood mononuclear cells (PBMC), T-cells and monocytes +/- recombinant leptin (rleptin), to assess leptin's direct effect on pro- and anti-inflammatory cytokine secretion. We found similar leptin and OB-Rs plasma levels between patients and controls. Untreated patients in the acute phase or in remission, or patients treated with methylprednisolone, had lower leptin levels than patients in the acute phase or in remission receiving IFN-beta. OB-Rs levels were low in patients refractory to IFN-beta but higher in patients receiving methylprednisolone or patients in remission receiving IFN-beta. PBMC from untreated patients in the acute phase, secreted spontaneously IFN-gamma, TNF-alpha and IL-10. IFN-gamma was contributed by T-cells, TNF-alpha and IL-10 primarily by monocytes and to a lesser extent by T-cells. The overall effect of rleptin on PBMC was a net increase in IL-10 production and a net reduction in IFN-gamma production. These results do not warrant a beneficial effect of fasting to MS patients.

Adult↗

Increasing leptin precedes craving and relapse during pharmacological abstinence maintenance treatment of alcoholism.

The appetite regulating peptide leptin has recently been associated with craving for alcohol and lifetime ethanol intake. However, effects of anti-craving drugs on leptin have not been studied until now. The objective of our study was to test the hypothesis whether leptin plasma concentration in abstinent alcohol addicts during treatment with naltrexone vs. acamprosate is associated with abstinence duration and craving for alcohol. Leptin plasma concentration was measured in 160 recently detoxified alcohol addicts during a double-blind, placebo-controlled relapse prevention trial with naltrexone vs. acamprosate vs. naltrexone plus acamprosate. During placebo treatment, increasing leptin plasma concentration was observed, whereas during combined treatment with naltrexone and acamprosate, leptin decreased significantly. The change from baseline of leptin plasma levels after weeks 4, 8 and 12 was inversely correlated with duration of abstinence and, after 4 weeks, positively correlated with self-rated craving. In summary, the study presents first evidence for an association of increasing leptin plasma concentrations with relapse to renewed alcohol intake in detoxified alcoholics. Moreover, there are hints for an interaction between pharmacological anti-craving treatment, plasma concentration of leptin, and abstinence duration.

Acamprosate↗

Inhibitory effects of an orexin-2 receptor antagonist on orexin A- and stress-induced ACTH responses in conscious rats.

Orexins, recognized for their diverse functions in sleep/wakefulness/arousal and appetite regulation, may play provocative roles in stress response. Although the PVN of the hypothalamus expresses an abundance of orexin-2 receptor (OX-2R), the involvement of OX-2R in regulating ACTH response to stress remains unclear. To address this, we examined effects of a selective antagonist to OX-2R (N-{(1S)-1-[6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]carbonyl}-2,2-dimethylpropyl)-N-{4-pyridinylmethyl}amine upon plasma ACTH concentrations after administration of orexin A and swimming stress. Increases in ACTH levels with orexin A or swimming stress were attenuated with prior administration of an OX-2R antagonist. These results suggest that swimming stress facilitates ACTH release, at least in part via activation of OX-2R.

Adrenocorticotropic Hormone↗

Neuropeptide Y, ubiquitous and elusive.

This paper reviews aspects of NPY research that were emerging in 1985, shortly after the isolation and characterization of the peptide. NPY had become known for its widespread distribution especially in the central and peripheral nervous systems, but also in the gastro-intestinal and respiratory tracts and in fibers innervating smooth muscle around blood vessels. Consistent with its distribution, it was determined that NPY is a potent vasoconstrictor, affects neuroendocrine systems and is involved in appetite regulation--areas of research still relevant today. Through advances in technology knowledge about NPY's role in these and newly discovered physiological functions has deepened considerably. Successful cloning of a series of NPY receptors has opened up new and complex research vistas. Lately, the creation of mice genetically modified for NPY as well as for several receptor subtypes has brought many puzzling observations--followed by questions yet to be answered.

Animals↗

Gene polymorphisms and their effects in the melanocortin system.

In addition to its role in human pigmentation, components of the melanocortin system regulate appetite, energy homeostasis and hormone production. Recent studies have suggested possible roles of this system in immunity, transmission of pain signals, and reproductive potential. A number of polymorphisms have been identified in genes of the melanocortin system and are associated with pigmentation in humans, as well as being causative of disorders of adrenal hormone production and obesity. This review gives an outline of these polymorphisms, their functional significance and possible application to or impact on diagnosis and pharmacotherapy based on melanocortin pathways.

Amino Acid Sequence↗

Neural interaction between galanin-like peptide (GALP)- and luteinizing hormone-releasing hormone (LHRH)-containing neurons.

Galanin-like peptide (GALP), commonly known as an appetite-regulating peptide, has been shown to increase plasma luteinizing hormone (LH) through luteinizing hormone-releasing hormone (LHRH). This led us to investigate, using both light and electron microscopy, whether GALP-containing neurons in the rat brain make direct inputs to LHRH-containing neurons. As LHRH-containing neurons are very difficult to demonstrate immunohistochemically with LHRH antiserum without colchicine treatment, we used a transgenic rat in which LHRH tagged with enhanced green fluorescence protein facilitated the precise detection of LHRH-producing neuronal cell bodies and processes. This is the first study to report on synaptic inputs to LHRH-containing neurons at the ultrastructural level using this transgenic model. We also used immunohistochemistry to investigate the neuronal interaction between GALP- and LHRH-containing neurons. The experiments revealed that GALP-containing nerve terminals lie in close apposition with LHRH-containing cell bodies and processes in the medial preoptic area and the bed nucleus of the stria terminalis. At the ultrastructural level, the GALP-positive nerve terminals were found to make axo-somatic and axo-dendritic synaptic contacts with the EGFP-positive neurons in these areas. These results strongly suggest that GALP-containing neurons provide direct input to LHRH-containing neurons and that GALP plays a crucial role in the regulation of LH secretion via LHRH.

Animals↗

Effects of chronic ICV leptin infusion on motor-activating effects of D-amphetamine in food-restricted and ad libitum fed rats.

Recently, attention has turned to the possibility that endocrine adiposity hormones, such as leptin, may regulate appetitively motivated behavior by modulating brain dopamine function. By extension, it has been hypothesized that the increased behavioral sensitivity of food-restricted, underweight rats to psychostimulant challenge may be triggered by the accompanying hypoleptinemia. The purpose of the present study was to determine whether two weeks of continuous intracerebroventricular (ICV) infusion of leptin alters the motor-activating effect of D-amphetamine (0.75 mg/kg, IP) in food-restricted rats. Lateral ventricular infusion of leptin, using a regimen that decreases food intake and body weight in ad libitum fed rats (12 microg/day), had no effect on the locomotor response to D-amphetamine in food-restricted rats that were maintained at 80% of prerestriction body weight. This result may indicate that hypoleptinemia is not involved in the induction/maintenance of neuroadaptations that mediate enhanced behavioral sensitivity to psychostimulant challenge. Interestingly, ad libitum fed rats treated with leptin displayed an increased locomotor response to D-amphetamine that was most prominent 3-5 days after termination of the infusion. Body weights and D-amphetamine sensitivity of these subjects returned to control values by 8-10 days postinfusion. The enhanced behavioral sensitivity to D-amphetamine in leptin-treated ad libitum fed rats may be a by-product of adipose depletion and, if so, would further support involvement of a peripheral signal other than hypoleptinemia in the modulation of central sensitivity to psychostimulant challenge.

Animals↗

Acute effects of an alcoholic drink on food intake: aperitif versus co-ingestion.

To compare the effects on appetite and energy intake (EI) within a meal and across 4 days of drinking wine either before (aperitif) or with (co-ingestion) a meal, 11 men attended the laboratory on three occasions. On each occasion participants were given breakfast in the laboratory then 3 h later returned for a two course (garlic bread, pizza) lunch, then recorded food intake for the remainder of the day and the next 3 days. In the control condition, participants ate lunch ad libitum; in the aperitif condition 375 ml of red wine was consumed 20 min before lunch; and in the co-ingestion condition 125 ml of red wine was consumed with the starter and 250 ml of red wine was consumed with the main course. Subjective ratings of appetite and mood were administered before and after the meal. EI at lunch was greater when wine was consumed (p<0.01) (aperitif: 6436+/-435 kJ; co-ingestion: 6254+/-417 kJ) compared to control (5125+/-262 kJ). In particular, intake of the starter was enhanced by wine consumption. Having wine as an aperitif significantly influenced subjective ratings of light headedness and fatigue. These results suggest that the effects of wine on appetite are immediate, and stimulate food intake early in the meal. Total EI during the test days was significantly higher than during subsequent days revealing a tendency to overeat in the laboratory, exacerbated by drinking wine before or with lunch. However, lean healthy men adjusted total EI on the days following the laboratory in all conditions.

Adolescent↗

Pharmacogenomics of antipsychotic-induced weight gain: A systematic review.

BACKGROUND: Antipsychotic-induced weight gain (AIWG) is a major clinical concern, affecting approximately 30% of patients. Clinical predictors explain only part of AIWG risk. Genetic and molecular variations are hypothesized to contribute to susceptibility. The purpose of this review is to summarize recent results to identify replicated and novel findings. STUDY DESIGN: Applying PRISMA guidelines, we searched MEDLINE, Embase, and PsycINFO (May 2018-May 2026) for studies on genetic and molecular associations with AIWG, extending our prior review. Reviews, editorials, and conference abstracts were excluded. We extracted study characteristics (design, diagnosis, antipsychotic exposure, sample size, ancestry, genetic variants, and AIWG outcomes) (e.g., &#x2265;7% weight gain, BMI change). RESULTS: Fifty-three studies met inclusion criteria. In candidate gene studies, the most consistently replicated genes associated with AIWG were observed for DRD2, HTR2C, and MC4R. Multiple novel associations were identified by genome-wide association studies (GWAS) (e.g., MAP2K1, ZDBF2, PEPD), polygenic risk scores (PRS) (e.g., body mass index PRS), gene expression (e.g., CYP3A4, EP300), and epigenetic analyses (e.g., cg12034943 at CRTC1). CONCLUSIONS: Polymorphisms in candidate genes related to neurotransmission and appetite regulation continue to be investigated for associations with AIWG, while novel findings have emerged from GWAS, gene expression, and epigenetic studies. Evidence remains inconsistent due to limited replication, methodological variability, sparse ancestry data, and geographical underrepresentation. No single genetic variant is ready for clinical use, and multi-omic and multi-ancestry models are needed to improve prediction and clinical utility.

Humans↗

Self-reported eating behaviors of extremely obese persons seeking bariatric surgery: a factor analytic approach.

OBJECTIVE: To summarize the self-reported eating behaviors of persons seeking bariatric surgery and to provide reliability data for a clinical instrument that assesses those eating behaviors. RESEARCH METHODS AND PROCEDURES: Adults (552) with extreme obesity (mean +/- standard deviation BMI = 52.4 +/- 10.1 kg/m2) completed the Weight and Lifestyle Inventory (WALI) before undergoing bariatric surgery. The WALI is a self-report instrument that includes 24 items that assess the eating behaviors to which respondents attribute their excess weight. These items were entered into a principal components analysis with promax rotation. Relationships of factor scores to demographic and psychosocial variables were examined. Test-retest reliability data were obtained from a smaller sample (n = 58) of less obese participants (BMI = 34.4 +/- 4.0 kg/m2) who completed the WALI twice within 2 weeks, before beginning a non-surgical weight loss program. RESULTS: The principal components analysis yielded five factors with acceptable internal consistency and test-retest reliability. These included: eating in response to negative affect, eating in response to positive affect and social cues, general overeating and impaired appetite regulation, overeating at early meals, and snacking. Each factor was related to symptoms of binge eating disorder, and every factor except the second one was associated with depressive symptoms. Factor scores were unrelated or weakly associated with demographic characteristics. DISCUSSION: The eating behaviors of persons seeking bariatric surgery can be assessed reliably and parsimoniously with the WALI. The predictive utility of the factors obtained in this study remains to be examined.

Adult↗

Relationship between leptin and bone mineral density in renal transplant recipients.

INTRODUCTION: Leptin plays an important role in regulating appetite and energy expenditure and also functions in the neuroendocrine, hematopoietic, and immune systems, among others. Leptin may be involved in modulating bone mineralization. The relationship between leptin and bone mineral density (BMD) is not clear. This study examined the relationship between BMD and serum leptin levels in renal transplant recipients. MATERIALS AND METHODS: Forty-one patients (28 men and 13 women; age 16 to 55 years) were grouped according to percentile of serum leptin level hypoleptinemic (<5th percentile, n = 14), normoleptinemic (between the 5th and 95th percentiles, n = 19), or hyperleptinemic (>95th percentile, n = 8). The patients also were grouped according to lumbar z score) and total femur z scores (>-2 vs <-2 for both). RESULTS: The groups with different leptin statuses were compared with respect to age, sex distribution, and body mass index. Mean lumbar z score and mean lumbar BMD were higher in the hyperleptinemic group than in the normo- and hypoleptinemic groups (P < .05 for all). Considering the 42 patients overall, those with lumbar z scores >-2 had higher mean serum leptin/BMI than those with lumbar z scores <-2 (0.55 +/- 0.65 vs 0.18 +/- 0.23, respectively, P < .05). Serum leptin/BMI ratio was correlated with lumbar z score (r = .38, P < .05) and lumbar BMD (r = .32, P < .05). CONCLUSION: In conclusion, the data indicate that elevated leptin level is associated with increased bone mass at lumbar sites in renal transplant recipients. This suggest that increased leptin has a bone-sparing effect, especially in the lumbar region, in this patient group.

Adolescent↗

Endogenous receptor for melanin-concentrating hormone in human neuroblastoma Kelly cells.

Melanin-concentrating hormone (MCH), a cyclic nonadecapeptide, is predominantly expressed in mammalian neurons located in the zona incerta and lateral hypothalamus. Current interest in MCH relates to its role in the control of feeding behaviour. Two receptors for MCH were recently found: MCH-R(1) and MCH-R(2). We show here by RT-PCR analysis and immunofluorescence studies that the human neuroblastoma cell line Kelly expresses MCH and MCH-R(1) but not MCH-R(2). In competition assays using 125I-labelled MCH an inhibitory concentration 50% (IC(50)) of 76nM was determined for MCH, indicating a high affinity of Kelly cells for MCH. MCH induces mitogen-activated protein kinase (MAPK) phosphorylation in Kelly cells but no increase in the intracellular free Ca(2+) concentration. This suggests that MCH signals via Galpha(i)/Galpha(0) in these cells. The presence and functionality of MCH-R(1) renders this neuronal cell a very useful model for future structure-activity studies in a physiological environment mimicking the human brain for the evaluation of potential appetite-regulating drugs.

Calcium Signaling↗