Efficacy of dietary supplements containing isolated organic compounds for weight loss: a systematic review and meta-analysis of randomised placebo-controlled trials.

BACKGROUND/OBJECTIVES: A systematic review with meta-analysis was conducted to synthesise evidence on the efficacy of dietary supplements containing isolated organic compounds for weight loss. SUBJECTS/METHODS: Four electronic databases (Medline, Embase, Web of Science, Cinahl) were searched until December 2019. Sixty-seven randomised placebo-controlled trials of dietary supplements containing isolated organic compounds for weight loss were included. Meta-analyses were conducted for chitosan, glucomannan, conjugated linoleic acid and fructans, comparing mean weight difference post-intervention between participants receiving the dietary supplement or placebo. RESULTS: Statistically significant weight differences compared to placebo were observed for chitosan (-1.84 kg; 95% confidence interval [CI] -2.79, -0.88; p < 0.01), glucomannan (-1.27 kg; 95%CI -2.45, -0.09; p = 0.04), and conjugated linoleic acid (-1.08 kg; 95%CI -1.61, -0.55; p < 0.01). None met our threshold for clinical significance (≥2.5 kg). There was no statistically significant effect on weight for fructans compared to placebo (p = 0.24). For dietary supplements with an inadequate number of trials for meta-analysis, a statistically and borderline clinically significant weight difference compared to placebo was found for modified cellulose, manno-oligosaccharides (in males), blood orange juice extract, and three multiple-ingredient dietary supplements. These were only reported in one trial of each. Thus, more evidence is needed before recommending them for weight loss. CONCLUSIONS: While some dietary supplements containing isolated organic compounds warrant further investigation to determine efficacy and safety, there is currently insufficient evidence to recommend any of these dietary supplements for weight loss.

Effectiveness of herbal medicines for weight loss: A systematic review and meta-analysis of randomized controlled trials.

AIM: To update the available evidence on the efficacy and safety of complementary medicines to assist in weight loss by conducting a systematic review and meta-analysis of herbal medicines for weight loss. METHODS: Four electronic databases (Medline, Embase, CINAHL and Web of Science) were searched from inception until August 2018. A total of 54 randomized placebo-controlled trials of healthy overweight or obese adults were identified. Meta-analyses were conducted for herbal medicines with ≥4 studies available. Weight differences of ≥2.5 kg were considered clinically significant. RESULTS: As a single agent, only Phaseolus vulgaris resulted in a statistically significant weight loss compared to placebo, although this was not considered clinically significant. No effect was seen for Camellia sinensis or Garcinia cambogia. Statistically, but not clinically, significant differences were observed for combination preparations containing C. sinensis, P. vulgaris or Ephedra sinica. Of the herbal medicines trialled in ≤3 randomized controlled trials, statistically and clinically significant weight loss compared to placebo was reported for Irvingia gabonensis, Cissus quadrangularis, and Sphaeranthus indicus combined with Garcinia mangostana, among others, but these findings should be interpreted cautiously because of the small number of studies, generally poor methodological quality, and poor reporting of the herbal medicine interventions. Most herbal medicines appeared safe for consumption over the short duration of the studies (commonly ≤12 weeks). Some warrant further investigation to determine effect size, dosage and long-term safety. CONCLUSION: There is currently insufficient evidence to recommend any of the herbal medicines for weight loss included in the present review.

Less Binge Eating and Loss of Control over Eating Are Associated with Greater Levels of Mindfulness: Identifying Patterns in Postmenopausal Women with Obesity.

Obesity is a public health concern resulting in widespread personal, social, and economic burden. Many individuals with obesity report feeling unable to stop eating or to control their food intake (i.e., a loss of control over eating) despite their best efforts. Experiencing loss of control over eating predicts further eating pathology and is a key feature of binge eating. Mindfulness (i.e., awareness and acceptance of current thoughts, feelings, sensations, and surrounding events) has emerged as a potential strategy to treat such eating disorder behaviors, but it is not known whether there is merit in investigating this strategy to address binge eating in postmenopausal women with obesity. Thus, this study aimed to examine the relationships between binge eating and mindfulness in postmenopausal women with obesity seeking weight loss treatment. Participants (n = 101) were assessed with the Eating Disorder Examination Questionnaire, the Loss of Control over Eating Scale, the Five-Facet Mindfulness Questionnaire, and the Langer Mindfulness Scale. Participants´ overall scores on both mindfulness scales were significantly and negatively correlated with binge eating frequency or the severity of loss of control over eating. Moreover, participants who reported fewer binge eating episodes were significantly more mindful than those who reported greater frequencies of binge eating episodes within the past 28 days. These findings suggest a merit in investigating the use of mindfulness-based therapies to treat binge eating in postmenopausal women with obesity.

Examining mindfulness as a predictor of weight loss - Findings from the DIABEGG study.

OBJECTIVE: Identifying individuals who are less likely to respond to a weight loss intervention allows better allocation or focus of resources to achieve better weight loss results. The current study investigated whether baseline levels of mindfulness would predict weight loss during a 12-month diet and exercise intervention. METHODS: The Five Facet Mindfulness Questionnaire (FFMQ) was administered and body weight measured, at baseline, three, six and 12 months in 140 participants with pre-diabetes or type 2 diabetes mellitus and a body mass index of ≥25kg/m2. 137 of 140 participants completed the FFMQ at baseline and were included in this study. RESULTS: There was no correlation between baseline mindfulness scores and weight loss. Mean baseline total FFMQ score was 112.2 [95% confidence interval: 109.4, 115.1] which did not change over the course of the study. Mean baseline body weight was 95.1kg (standard deviation (19.1kg)). There was a significant decrease in weight at month 12 (-3.8kg (±standard deviation 5.8kg)). This is comparable to the weight loss achieved by participants in other interventions of the same duration. CONCLUSIONS: The findings suggest that baseline dispositional mindfulness does not predict the amount of weight loss in a lifestyle (diet and exercise) intervention.

Intermittent Moderate Energy Restriction Improves Weight Loss Efficiency in Diet-Induced Obese Mice.

BACKGROUND: Intermittent severe energy restriction is popular for weight management. To investigate whether intermittent moderate energy restriction may improve this approach by enhancing weight loss efficiency, we conducted a study in mice, where energy intake can be controlled. METHODS: Male C57/Bl6 mice that had been rendered obese by an ad libitum diet high in fat and sugar for 22 weeks were then fed one of two energy-restricted normal chow diets for a 12-week weight loss phase. The continuous diet (CD) provided 82% of the energy intake of age-matched ad libitum chow-fed controls. The intermittent diet (ID) provided cycles of 82% of control intake for 5-6 consecutive days, and ad libitum intake for 1-3 days. Weight loss efficiency during this phase was calculated as (total weight change) ÷ [(total energy intake of mice on CD or ID)-(total average energy intake of controls)]. Subsets of mice then underwent a 3-week weight regain phase involving ad libitum re-feeding. RESULTS: Mice on the ID showed transient hyperphagia relative to controls during each 1-3-day ad libitum feeding period, and overall ate significantly more than CD mice (91.1±1.0 versus 82.2±0.5% of control intake respectively, n = 10, P<0.05). There were no significant differences between CD and ID groups at the end of the weight loss or weight regain phases with respect to body weight, fat mass, circulating glucose or insulin concentrations, or the insulin resistance index. Weight loss efficiency was significantly greater with ID than with CD (0.042±0.007 versus 0.018±0.001 g/kJ, n = 10, P<0.01). Mice on the CD exhibited significantly greater hypothalamic mRNA expression of proopiomelanocortin (POMC) relative to ID and control mice, with no differences in neuropeptide Y or agouti-related peptide mRNA expression between energy-restricted groups. CONCLUSION: Intermittent moderate energy restriction may offer an advantage over continuous moderate energy restriction, because it induces significantly greater weight loss relative to energy deficit in mice.

Comparing cognitive behavioural therapy for eating disorders integrated with behavioural weight loss therapy to cognitive behavioural therapy-enhanced alone in overweight or obese people with bulimia nervosa or binge eating disorder: study protocol for a randomised controlled trial.

BACKGROUND: Around 40 % of individuals with eating disorders of recurrent binge eating, namely bulimia nervosa and binge eating disorder, are obese. In contrast to binge eating disorder, currently there is no evidence base for weight management or weight loss psychological therapies in the treatment of bulimia nervosa despite their efficacy in binge eating disorder. Thus, a manualised therapy called HAPIFED (Healthy APproach to weIght management and Food in Eating Disorders) has been developed. HAPIFED integrates the leading evidence-based psychological therapies, cognitive behavioural therapy-enhanced (CBT-E) and behavioural weight loss treatment (BWLT) for binge eating disorder and obesity respectively. The aim of the present study is to detail the protocol for a randomised controlled trial (RCT) of HAPIFED versus CBT-E for people with bulimia nervosa and binge eating disorder who are overweight/obese. METHOD/DESIGN: A single-blind superiority RCT is proposed. One hundred Brazilian participants aged ≥ 18 years, with a diagnosis of bulimia nervosa or binge eating disorder, BMI > 27 to < 40 kg/m(2), will be recruited from both community and clinics and individually randomised to a therapy arm. Five groups of ten participants will receive the experimental intervention (HAPIFED) and the other five groups of ten the control intervention (CBT-E). Both therapies are manualised, and in this RCT will comprise 1 individual session and 29 office-based group sessions over 6 months. Assessment points will be at baseline, end of therapy, and 6 and 12 months after end of therapy. The primary outcome of this intervention will be reduced weight. Secondary outcomes will be improved metabolic indicators of weight management, reduction in eating disorder symptoms including improved control over eating, improved adaptive function, physical and mental health-related quality of life, and reduced levels of depression and anxiety. DISCUSSION: This study will be the first to investigate a psychological therapy that aims to assist weight management in people with co-morbid overweight or obesity bulimia nervosa as well as with binge eating disorder. It will have the potential to improve health outcomes for the rapidly increasing number of adults with co-morbid obesity and binge eating disorder or bulimia nervosa. TRIAL REGISTRATION: US National Institutes of Health clinical trial registration number NCT02464345 , date of registration 1 June 2015.

The role of pancreatic polypeptide in the regulation of energy homeostasis.

Imbalances in normal regulation of food intake can cause obesity and related disorders. Inadequate therapies for such disorders necessitate better understanding of mechanisms that regulate energy homeostasis. Pancreatic polypeptide (PP), a robust anorexigenic hormone, effectively modulates food intake and energy homeostasis, thus potentially aiding anti-obesity therapeutics. Intra-gastric and intra-intestinal infusion of nutrients stimulate PP secretion from the gastrointestinal tract, leading to vagal stimulation that mediates complex actions via the neuropeptide Y4 receptor in arcuate nucleus of the hypothalamus, subsequently activating key hypothalamic nuclei and dorsal vagal complex of the brainstem to influence energy homeostasis and body composition. Novel studies indicate affinity of PP for the relatively underexplored neuropeptide y6 receptor, mediating actions via the suprachiasmatic nucleus and pathways involving vasoactive intestinal polypeptide and insulin like growth factor 1. This review highlights detailed mechanisms by which PP mediates its actions on energy balance through various areas in the brain.

Glycyrrhizic acid can attenuate metabolic deviations caused by a high-sucrose diet without causing water retention in male Sprague-Dawley rats.

Glycyrrhizic acid (GA) ameliorates many components of the metabolic syndrome, but its potential therapeutic use is marred by edema caused by inhibition of renal 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2). We assessed whether 100 mg/kg per day GA administered orally could promote metabolic benefits without causing edema in rats fed on a high-sucrose diet. Groups of eight male rats were fed on one of three diets for 28 days: normal diet, a high-sucrose diet, or a high-sucrose diet supplemented with GA. Rats were then culled and renal 11ß-HSD2 activity, as well as serum sodium, potassium, angiotensin II and leptin levels were determined. Histological analyses were performed to assess changes in adipocyte size in visceral and subcutaneous depots, as well as hepatic and renal tissue morphology. This dosing paradigm of GA attenuated the increases in serum leptin levels and visceral, but not subcutaneous adipocyte size caused by the high-sucrose diet. Although GA decreased renal 11ß-HSD2 activity, it did not affect serum electrolyte or angiotensin II levels, indicating no onset of edema. Furthermore, there were no apparent morphological changes in the liver or kidney, indicating no toxicity. In conclusion, it is possible to reap metabolic benefits of GA without edema using the current dosage and treatment time.

The endogenous opioid dynorphin is required for normal bone homeostasis in mice.

Chronic opiate usage, whether prescribed or illicit, has been associated with changes in bone mass and is a recognized risk factor for the development of osteoporosis; however, the mechanism behind this effect is unknown. Here we show that lack of dynorphin, an endogenous opioid, in mice (Dyn-/-), resulted in a significantly elevated cancellous bone volume associated with greater mineral apposition rate and increased resorption indices. A similar anabolic phenotype was evident in bone of mice lacking dynorphin's cognate receptor, the kappa opioid receptor. Lack of opioid receptor expression in primary osteoblastic cultures and no change in bone cell function after dynorphin agonist treatment in vitro indicates an indirect mode of action. Consistent with a hypothalamic action, central dynorphin signaling induces extracellular signal-regulated kinase (ERK) phosphorylation and c-fos activation of neurons in the arcuate nucleus of the hypothalamus (Arc). Importantly, this signaling also leads to an increase in Arc NPY mRNA expression, a change known to decrease bone formation. Further implicating NPY in the skeletal effects of dynorphin, Dyn-/-/NPY-/- double mutant mice showed comparable increases in bone formation to single mutant mice, suggesting that dynorphin acts upstream of NPY signaling to control bone formation. Thus the dynorphin system, acting via NPY, may represent a pathway by which higher processes including stress, reward/addiction and depression influence skeletal metabolism. Moreover, understanding of these unique interactions may enable modulation of the adverse effects of exogenous opioid treatment without directly affecting analgesic responses.

Y1 and Y5 receptors are both required for the regulation of food intake and energy homeostasis in mice.

Neuropeptide Y (NPY) acting in the hypothalamus is one of the most powerful orexigenic agents known. Of the five known Y receptors, hypothalamic Y1 and Y5 have been most strongly implicated in mediating hyperphagic effects. However, knockout of individual Y1 or Y5 receptors induces late-onset obesity--and Y5 receptor knockout also induces hyperphagia, possibly due to redundancy in functions of these genes. Here we show that food intake in mice requires the combined actions of both Y1 and Y5 receptors. Germline Y1Y5 ablation in Y1Y5(-/-) mice results in hypophagia, an effect that is at least partially mediated by the hypothalamus, since mice with adult-onset Y1Y5 receptor dual ablation targeted to the paraventricular nucleus (PVN) of the hypothalamus (Y1Y5(Hyp/Hyp)) also exhibit reduced spontaneous or fasting-induced food intake when fed a high fat diet. Interestingly, despite hypophagia, mice with germline or hypothalamus-specific Y1Y5 deficiency exhibited increased body weight and/or increased adiposity, possibly due to compensatory responses to gene deletion, such as the decreased energy expenditure observed in male Y1Y5(-/-) animals relative to wildtype values. While Y1 and Y5 receptors expressed in other hypothalamic areas besides the PVN--such as the dorsomedial nucleus and the ventromedial hypothalamus--cannot be excluded from having a role in the regulation of food intake, these studies demonstrate the pivotal, combined role of both Y1 and Y5 receptors in the mediation of food intake.

Y2 and Y4 receptor signalling attenuates the skeletal response of central NPY.

Both the neuropeptide Y (NPY) and the leptin systems have been shown to be important central mediators of bone metabolism. However, the interaction between these two systems is complex and not fully understood. Here, we show that a unique interaction exists between Y2 and Y4 receptors in the regulation of bone homeostasis that is not evident when combined with lack of Y1 signalling. Despite the hypoleptinaemia shown in male Y2/Y4 double knockout (Y2⁻/⁻ Y4⁻/⁻) mice, when on the leptin-deficient ob/ob background, these mice display reduced cancellous bone mass. However, combined Y2/Y4 deletion enhances the effect of leptin deficiency on the cortical bone compartment. By replicating the enhanced central NPY expression evident in ob/ob mice using virally mediated overexpression of NPY in the hypothalamus of Y receptor knockout mice, we demonstrate that Y2⁻/⁻ Y4⁻/⁻ mice have an exaggerated response to the anti-osteogenic effects of elevated hypothalamic NPY in both cancellous and cortical bone and that this effect appears to be dependent on Y1 receptor signalling. This study highlights the complex interaction between Y receptors in the control of bone mass. Moreover, it suggests that the reduction in cortical bone observed in the absence of leptin is due to the anti-osteogenic effect of elevated hypothalamic NPY levels.

Neuropeptide Y and sex hormone interactions in humoral and neuronal regulation of bone and fat.

The hypothalamus regulates the skeleton and adipose tissue via endocrine mechanisms. Changes in sex steroid levels in menopause and aging are central to the associated changes in bone mass and adiposity. Whereas many of these effects occur via direct actions on osteoblasts or adipocytes, sex hormones can also mediate effects on bone and adipose tissue via interaction with neuronal pathways. A key hypothalamic regulator of bone and adipose tissue is neuropeptide Y (NPY), which coordinately influences these tissues via effects on neuroendocrine and sympathetic nervous output. Better understanding of the interaction between NPY and sex steroids in regulating skeletal and energy homeostasis could lead to more effective treatments for osteoporosis and obesity.

Neuropeptide Y knockout mice reveal a central role of NPY in the coordination of bone mass to body weight.

Changes in whole body energy levels are closely linked to alterations in body weight and bone mass. Here, we show that hypothalamic signals contribute to the regulation of bone mass in a manner consistent with the central perception of energy status. Mice lacking neuropeptide Y (NPY), a well-known orexigenic factor whose hypothalamic expression is increased in fasting, have significantly increased bone mass in association with enhanced osteoblast activity and elevated expression of bone osteogenic transcription factors, Runx2 and Osterix. In contrast, wild type and NPY knockout (NPY (-/-)) mice in which NPY is specifically over expressed in the hypothalamus (AAV-NPY+) show a significant reduction in bone mass despite developing an obese phenotype. The AAV-NPY+ induced loss of bone mass is consistent with models known to mimic the central effects of fasting, which also show increased hypothalamic NPY levels. Thus these data indicate that, in addition to well characterized responses to body mass, skeletal tissue also responds to the perception of nutritional status by the hypothalamus independently of body weight. In addition, the reduction in bone mass by AAV NPY+ administration does not completely correct the high bone mass phenotype of NPY (-/-) mice, indicating the possibility that peripheral NPY may also be an important regulator of bone mass. Indeed, we demonstrate the expression of NPY specifically in osteoblasts. In conclusion, these data identifies NPY as a critical integrator of bone homeostatic signals; increasing bone mass during times of obesity when hypothalamic NPY expression levels are low and reducing bone formation to conserve energy under 'starving' conditions, when hypothalamic NPY expression levels are high.

Novel role of Y1 receptors in the coordinated regulation of bone and energy homeostasis.

The importance of neuropeptide Y (NPY) and Y2 receptors in the regulation of bone and energy homeostasis has recently been demonstrated. However, the contributions of the other Y receptors are less clear. Here we show that Y1 receptors are expressed on osteoblastic cells. Moreover, bone and adipose tissue mass are elevated in Y1(-/-) mice with a generalized increase in bone formation on cortical and cancellous surfaces. Importantly, the inhibitory effects of NPY on bone marrow stromal cells in vitro are absent in cells derived from Y1(-/-) mice, indicating a direct action of NPY on bone cells via this Y receptor. Interestingly, in contrast to Y2 receptor or germ line Y1 receptor deletion, conditional deletion of hypothalamic Y1 receptors in adult mice did not alter bone homeostasis, food intake, or adiposity. Furthermore, deletion of both Y1 and Y2 receptors did not produce additive effects in bone or adiposity. Thus Y1 receptor pathways act powerfully to inhibit bone production and adiposity by nonhypothalamic pathways, with potentially direct effects on bone tissue through a single pathway with Y2 receptors.

Hypothalamic regulation of cortical bone mass: opposing activity of Y2 receptor and leptin pathways.

UNLABELLED: NeuropeptideY-, Y2 receptor (Y2)-, and leptin-deficient mice show similar anabolic action in cancellous bone but have not been assessed in cortical bone. Cortical bone mass is elevated in Y2(-/-) mice through greater osteoblast activity. In contrast, leptin deficiency results in reduced bone mass. We show opposing central regulation of cortical bone. INTRODUCTION: Treatment of osteoporosis is confounded by a lack of agents capable of stimulating the formation of bone by osteoblasts. Recently, the brain has been identified as a potent anabolic regulator of bone formation. Hypothalamic leptin or Y2 receptor signaling are known to regulate osteoblast activity in cancellous bone. However, assessment of these pathways in the structural cortical bone is critical to understanding their role in skeletal health and their potential clinical relevance to osteoporosis and its treatment. MATERIALS AND METHODS: Long bones of 16-week male ob/ob and germline and hypothalamic Y2(-/-) mice were assessed by QCT. Cortical osteoblast activity was assessed histologically. RESULTS: The femora of skeletally mature Y2(-/-) mice and of leptin-deficient ob/ob and Y2(-/-)ob/ob mice were assessed for changes in cortical osteoblast activity and bone mass. Ablation of Y2 receptors increased osteoblast activity on both endosteal and periosteal surfaces, independent of leptin, resulting in increased cortical bone mass and density in Y2(-/-) mice along the entire femur. Importantly, these changes were evident after deletion of hypothalamic Y2 receptors in adult mice, with a 5-fold elevation in periosteal bone formation. This is in marked contrast to leptin-deficient models that displayed reduced cortical mass and density. These changes were associated with substantial differences in calculated strength between the Y2(-/-) and leptin-deficient mice. CONCLUSIONS: These results indicate that the Y2-mediated anabolic pathway stimulates cortical and cancellous bone formation, whereas the leptin-mediated pathway has opposing effects in cortical and cancellous bone, diminishing the production of cortical bone. The findings from conditional hypothalamic Y2 knockout show a novel, inducible control mechanism for cortical bone formation and a potential new pathway for anabolic treatment of osteoporosis.

Combined deletion of Y1, Y2, and Y4 receptors prevents hypothalamic neuropeptide Y overexpression-induced hyperinsulinemia despite persistence of hyperphagia and obesity.

Neuropeptide Y (NPY) is a key regulator of energy homeostasis and is implicated in the development of obesity and type 2 diabetes. Whereas it is known that hypothalamic administration of exogenous NPY peptides leads to increased body weight gain, hyperphagia, and many hormonal and metabolic changes characteristic of an obesity syndrome, the Y receptor(s) mediating these effects is disputed and unclear. To investigate the role of different Y receptors in the NPY-induced obesity syndrome, we used recombinant adeno-associated viral vector to overexpress NPY in mice deficient of selective single or multiple Y receptors (including Y1, Y2, and Y4). Results from this study demonstrated that long-term hypothalamic overexpression of NPY lead to marked hyperphagia, hypogonadism, body weight gain, enhanced adipose tissue accumulation, hyperinsulinemia, and other hormonal changes characteristic of an obesity syndrome. NPY-induced hyperphagia, hypogonadism, and obesity syndrome persisted in all genotypes studied (Y1(-/-), Y2(-/-), Y2Y4(-/-), and Y1Y2Y4(-/-) mice). However, triple deletion of Y1, Y2, and Y4 receptors prevented NPY-induced hyperinsulinemia. These findings suggest that Y1, Y2, and Y4 receptors under this condition are not crucially involved in NPY's hyperphagic, hypogonadal, and obesogenic effects, but they are responsible for the central regulation of circulating insulin levels by NPY.

Conditional deletion of hypothalamic Y2 receptors reverts gonadectomy-induced bone loss in adult mice.

Reduction in levels of sex hormones at menopause in women is associated with two common, major outcomes, the accumulation of white adipose tissue, and the progressive loss of bone because of excess osteoclastic bone resorption exceeding osteoblastic bone formation. Current antiresorptive therapies can reduce osteoclastic activity but have only limited capacity to stimulate osteoblastic bone formation and restore lost skeletal mass. Likewise, the availability of effective pharmacological weight loss treatments is currently limited. Here we demonstrate that conditional deletion of hypothalamic neuropeptide Y2 receptors can prevent ongoing bone loss in sex hormone-deficient adult male and female mice. This benefit is attributable solely to activation of an anabolic osteoblastic bone formation response that counterbalances persistent elevation of bone resorption, suggesting the Y2-mediated anabolic pathway to be independent of sex hormones. Furthermore, the increase in fat mass that typically occurs after ovariectomy is prevented by germ line deletion of Y2 receptors, whereas in male mice body weight and fat mass were consistently lower than wild-type regardless of sex hormone status. Therefore, this study indicates a role for Y2 receptors in the accumulation of adipose tissue in the hypogonadal state and demonstrates that hypothalamic Y2 receptors constitutively restrain osteoblastic activity even in the absence of sex hormones. The increase in bone formation after release of this tonic inhibition suggests a promising new avenue for osteoporosis treatment.

Y2Y4 receptor double knockout protects against obesity due to a high-fat diet or Y1 receptor deficiency in mice.

Neuropeptide Y receptors are critical regulators of energy homeostasis, but the functional interactions and relative contributions of Y receptors and the environment in this process are unknown. We measured the effects of an ad libitum diet of normal or high-fat food on energy balance in mice with single, double, or triple deficiencies of Y1, Y2, or Y4 receptors. Whereas wild-type mice developed diet-induced obesity, Y2Y4 double knockouts did not. In contrast, Y1 knockout or Y1Y2 or Y1Y4 receptor double knockout mice developed an exacerbated diet-induced obesity syndrome. Remarkably, the antiobesity effect of Y2Y4 deficiency was stronger than the obesogenic effect of Y1 deficiency, since Y1Y2Y4 triple knockouts did not develop obesity on the high-fat diet. Resistance to diet-induced obesity in Y2Y4 knockouts was associated with reduced food intake and improved glucose tolerance in the absence of changes in total physical activity. Fecal concentration of free fatty acids was significantly increased in Y2Y4 knockouts in association with a significantly reduced bile acid pool and marked alterations in intestinal morphology. In addition, hypothalamic proopiomelanocortin expression was decreased in diet-induced obesity (in both wild-type and Y1 receptor knockout mice) but not in obesity-resistant Y2Y4 receptor knockout mice fed a high-fat diet. Therefore, deletion of Y2 and Y4 receptors synergistically protects against diet-induced obesity, at least partially via changes in food intake and hypothalamic proopiomelanocortin expression.

Hypothalamic control of bone formation: distinct actions of leptin and y2 receptor pathways.

UNLABELLED: Leptin and Y2 receptors on hypothalamic NPY neurons mediate leptin effects on energy homeostasis; however, their interaction in modulating osteoblast activity is not established. Here, direct testing of this possibility indicates distinct mechanisms of action for leptin anti-osteogenic and Y2-/- anabolic pathways in modulating bone formation. INTRODUCTION: Central enhancement of bone formation by hypothalamic neurons is observed in leptin-deficient ob/ob and Y2 receptor null mice. Similar elevation in central neuropeptide Y (NPY) expression and effects on osteoblast activity in these two models suggest a shared pathway between leptin and Y2 receptors in the central control of bone physiology. The aim of this study was to test whether the leptin and Y2 receptor pathways regulate bone by the same or distinct mechanisms. MATERIALS AND METHODS: The interaction of concomitant leptin and Y2 receptor deficiency in controlling bone was examined in Y2-/- ob/ob double mutant mice, to determine whether leptin and Y2 receptor deficiency have additive effects. Interaction between leptin excess and Y2 receptor deletion was examined using recombinant adeno-associated viral vector overproduction of NPY (AAV-NPY) to produce weight gain and thus leptin excess in adult Y2-/- mice. Cancellous bone volume and bone cell function were assessed. RESULTS: Osteoblast activity was comparably elevated in ob/ob, Y2-/-, and Y2-/- ob/ob mice. However, greater bone resorption in ob/ob and Y2-/- ob/ob mice reduced cancellous bone volume compared with Y2-/-. Both wildtype and Y2-/- AAV-NPY mice exhibited marked elevation of white adipose tissue accumulation and hence leptin expression, thereby reducing osteoblast activity. Despite this anti-osteogenic leptin effect in the obese AAV-NPY model, osteoblast activity in Y2-/- AAV-NPY mice remained significantly greater than in wildtype AAV-NPY mice. CONCLUSIONS: This study suggests that NPY is not a key regulator of the leptin-dependent osteoblast activity, because both the leptin-deficient stimulation of bone formation and the excess leptin inhibition of bone formation can occur in the presence of high hypothalamic NPY. The Y2-/- pathway acts consistently to stimulate bone formation; in contrast, leptin continues to suppress bone formation as circulating levels increase. As a result, they act increasingly in opposition as obesity becomes more marked. Thus, in the absence of leptin, the cancellous bone response to loss of Y2 receptor and leptin activity can not be distinguished. However, as leptin levels increase to physiological levels, distinct signaling pathways are revealed.

Hypothalamic regulation of energy homeostasis.

The co-ordinated regulation of food intake and energy expenditure takes place in the hypothalamic regions of the brain. Current understanding of the systems involved in this regulation suggests that, in the hypothalamus, there are two major groups of neuropeptides involved in orexigenic and anorexic processes. The orexigenic neuropeptides are neuropeptide Y (NPY) and agouti-related peptide (AgRP) and the anorexic neuropeptides are alpha-melanocyte-stimulating hormone (alpha-MSH) and cocaine and amphetamine-related transcript (CART). Theneurons expressing these neuropeptides interact with each other and with signals from the periphery (such as leptin, insulin, ghrelin and glucocorticoids) to regulate feeding behaviour, energy expenditure and various endocrine axes. Although direct evidence is limited, there are examples of genetic obesity in humans which suggest that the balance between orexigenic and anorexic pathways in the hypothalamus is also pivotally important in the maintenance of energy homeostasis in humans.