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Introduction: An orally administered amino acid-based test supplement was recently shown to increase human growth hormone (hGH) in healthy adults. This prospective, observational, single-center, single-arm cohort study investigated the effects of 24 weeks of daily oral administration of the test supplement in individuals with stress-related weight gain, fibromyalgia (FM) and stress-related low-normal hGH production (15-30 th percentile for age-appropriate levels) on insulin-like growth factor 1 (IGF-1), an indicator of hGH levels caused by stress related stimulation of somatostatin., Methods: Participants continued to receive standard care. The primary endpoint was the change from baseline to endpoint (Week 24) in serum IGF-1. Additional endpoints included the change in body weight, clinical symptoms (assessed with the Revised Fibromyalgia Impact Questionnaire [FIQR], range 0-100, and Perceived Stress Scale [PSS], range 0-40), fasting cardiometabolic markers, tolerability, and safety. The study enrolled 84 fibromyalgia patients with low-normal age-adjusted IGF-1 serum levels. High mean ± Standard Deviation (SD) baseline FIQR and PSS scores of 76 ± 16 and 32 ± 5, respectively, indicated poor to moderate symptom management with standard care. All individuals completed 24 weeks., Results: Serum IGF-1 levels increased with a Week 24 mean± Standard Error (SE) change of 28.4 ± 3.0 ng/mL ( p <0.001). Body weight was reduced with a Week 24 mean ± SE change of -5.5 ± 0.3 kg ( p <0.001) (a 6.5% weight loss from baseline). The change from baseline in FIQR and PSS scores were -29.1 ± 1.1 and -20.0 ± 0.8, respectively (both p <0.001), indicating a substantial improvement. Statistically significant improvements from baseline to Week 24 were observed in systolic and diastolic blood pressure, HbA1c, LDL and HDL cholesterol, and triglycerides (all p <0.001). The supplement was well tolerated; no adverse events were reported., Discussion: Sustained augmentation of IGF-1 with the test supplement may represent a novel method of improving clinical symptoms, including stress-related weight gain, in individuals with fibromyalgia and stress-associated low-normal hGH., Competing Interests: AH was employed by Sierra Research Group and some samples of the test supplement were provided by Sierra Research Group. Authors SP and AB were employed by Professional Medical Corporation. Author CK was employed by Kelly Statistical Consulting. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pekarovics, Beres, Kelly, Billes and Heaton.)

Background: Time restricted eating (TRE) is an emerging dietary intervention for weight loss that is hypothesized to reinforce the metabolic benefits of nightly fasting/ketosis. This pilot study investigated the effectiveness of a daily 14-h metabolic fast (14:10 TRE beginning after dinner, a "fasting snack" at hour 12, and ending with breakfast 14 h later) combined with a commercial weight management program on body weight and fasting blood glucose (FBG) in individuals with obesity. We also investigated the effect of the low-calorie, high-fat, low-carbohydrate, and low-protein "fasting snack" on blood glucose., Methods: This 8-week, randomized, controlled, clinical trial included men and women (BMI ≥ 30 kg/m 2 ) between June and October 2020. Study procedures were conducted remotely. Participants were randomized to 14:10 or 12-h TRE (12:12, active comparator) and prescribed a diet (controlled for calories and macronutrient composition) and exercise program that included weekly customized counseling and support. The primary outcome was change from baseline in body weight in the 14:10 group., Results: Of the 78 randomized participants, 60 (n = 30/group) completed 8 weeks. The LS mean change from baseline in weight in the 14:10 group was -8.5% (95% CI -9.6 to -7.4; P < 0.001) and -7.1% (-8.3 to -5.8; P < 0.001) in the 12:12 group (between group difference -1.4%; -2.7 to -0.2; P < 0.05). There was a statistically significant LS mean change from baseline to week 8 in FBG in the 14:10 group of -7.6 mg/dl (95% CI -15.1 to -0.1; P < 0.05) but not in the 12:12 group (-3.1 mg/dl, -10.0 to 3.7; P = NS). Both interventions resulted in a larger reduction in FBG in participants with elevated FBG (≥100 mg/dl) at baseline (both P < 0.05)., Conclusions: In participants with obesity who completed 8 weeks of the 14:10 TRE schedule combined with a commercial weight loss program, there was statistically significant and clinically meaningful weight loss and improvements in FBG.

The mechanism of action of the combination therapy, naltrexone/bupropion (NB), for obesity has not been fully described to date. Weight loss attempts rarely result in long-term success. This is likely a result of complex interactions among multiple peripheral and CNS systems that defend against weight loss, and may explain the overwhelming lack of effective obesity treatments. NB is an investigational combination therapy for obesity that was developed based on evidence that obesity involves alterations in the hypothalamic melanocortin system as well as brain reward systems that influence food craving and mood. Naltrexone and bupropion both have actions in these brain regions that may cause them to influence food intake, food craving, and other aspects of eating behavior that affect body weight. We review the individual actions of naltrexone and bupropion in brain hypothalamic and reward systems, and describe the current in vitro, in vivo, and clinical evidence for how NB influences food intake and produces weight loss., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The effects of combination naltrexone/bupropion therapy on body composition and visceral adipose tissue (VAT) mass were examined in a subset (n = 107) of obese subjects from a Phase 2 trial that compared the efficacy and safety of placebo, naltrexone monotherapy, bupropion monotherapy or one of three naltrexone/bupropion dose combinations for 24 weeks. Body composition data were obtained using dual-energy X-ray absorptiometry and computed tomography. Eighty subjects completed the substudy. Naltrexone/bupropion resulted in weight loss and a greater reduction in body fat (-14.0 ± 1.3%) than placebo (-4.0 ± 2.0%), naltrexone monotherapy (-3.2 ± 2.5%) and bupropion monotherapy (-4.1 ± 2.9%; all p < 0.01). Reduction in VAT mass was also greater with naltrexone/bupropion (-15.0 ± 1.8%) than placebo (-4.6 ± 2.7%), naltrexone monotherapy (-0.1 ± 3.5%) and bupropion monotherapy (-2.3 ± 4.2%; all p < 0.01). Reductions in body fat and VAT mass with naltrexone/bupropion were proportional with weight loss. Weight loss with naltrexone/bupropion was not associated with a greater relative reduction in lean mass than placebo or the monotherapies., (© 2013 Blackwell Publishing Ltd.)

Food intake is generally accepted to be regulated by the melanocortin system, however recent data suggests that mesolimbic dopaminergic neurons also influence food intake. Whether dopamine signaling is crucial for the acute effect of leptin on feeding is unknown. Using pharmacological and genetic strategies, we tested the hypothesis that the acute inhibitory effect of leptin on food intake is partially mediated by dopamine. Dopamine D2 but not D1 receptor blockade attenuated the acute hypophagic effect of leptin in fasted mice. Additionally, mice lacking the D2R (D2R KO) exhibited an attenuated response to leptin. Conversely, dopamine receptor blockade had no effect on the acute hypophagic effect of melanocortin stimulation or the hyperphagic effect of ghrelin. These findings suggest that dopaminergic pathways do not constitute a normal part of melanocortin-dependent feeding regulation and that the dopaminergic neurocircuitry typically associated with regulation of hedonic feeding likely contributes to feeding regulation by leptin.

Introduction: Although pharmacological treatments for obesity represent only one option in managing obesity, they are a useful tool in an otherwise extremely limited armamentarium. Naltrexone/bupropion combination therapy was developed by using technological advances that have improved our understanding of how the brain regulates body weight., Areas Covered: This review covers the development of naltrexone/bupropion combination therapy for obesity, as well as the published clinical trials on the safety and efficacy of the combination in overweight and obese humans. The effect of naltrexone/bupropion on food craving seems to be unique, and the implications of this finding for weight loss are discussed., Expert Opinion: Safety and tolerability issues seem to be manageable and consistent with the documented effects of each component. Appropriate patient management should address the mild sympathomimetic effect of bupropion, although the FDA has required that a cardiovascular outcomes study be conducted preapproval to determine the effects of long-term use of naltrexone/bupropion in an overweight/obese population. When used in conjunction with diet and exercise, the naltrexone/bupropion combination may be a useful treatment option for obesity, especially for overweight and obese adults who report difficulty controlling eating behavior and their response to food cravings.

A combination of sustained release (SR) naltrexone (32 mg/day) and bupropion SR (360 mg/day) plus behavioral counseling was evaluated for the treatment of smoking cessation and mitigation of nicotine withdrawal and weight gain. Thirty overweight or obese nicotine-dependent subjects were enrolled in a 24-week, open-label study; 85% and 63% completed 12 and 2 4weeks, respectively. The target quit date was Week 4. Week 4-12 continuous abstinence rate was 48%, 78% of subjects achieved CO < or = 10 ppm, serum cotinine decreased from 185 to 48 microg/L, and tobacco use decreased from 129 to 14 cigarettes/week. Similar results were seen at Week 24. Body weight was essentially unchanged (Week 12: -0.1%; Week 24: +0.4%). Except for a transient significant increase 1 week after the target quit date (p<0.05), nicotine withdrawal scores did not change. The most common adverse events were nausea, insomnia, and constipation. These tended to be transient and mild or moderate in severity. In overweight or obese smokers, naltrexone/bupropion combination therapy with behavioral counseling was associated with decreased nicotine use, limited nicotine withdrawal symptoms, and no significant weight gain., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Bupropion (BUP) is a dopamine (DA) and norepinephrine (NE) reuptake inhibitor that causes mild weight loss in obese adults. Subchronic (7 day) coadministration of selective DA and NE reuptake inhibitors also causes weight loss in mice. Because weight loss was not associated with decreased caloric intake, subchronic BUP might cause weight loss through increased energy expenditure. Acute studies demonstrate that BUP or DA+NE reuptake inhibitors cause transient hypophagia and increased locomotion; though the effects on temperature are inconsistent. Because subchronic DA+NE reuptake inhibition does not affect appetite, there is clearly a difference between the acute and subchronic effects of DA+NE reuptake inhibitors; however the effects of chronic (or subchronic) BUP on energy balance have never been directly studied in an animal model. Therefore, the acute and subchronic effects of BUP or selective DA and NE reuptake inhibitors on food intake, body weight, locomotor activity, and interscapular temperature were determined in mice. Generally, selective inhibition of DA reuptake (by GBR12783) increased activity while selective inhibition of NE reuptake (by nisoxetine, NIS) decreased activity and temperature. BUP increased activity and temperature but subchronic BUP did not significantly reduce body weight due to a compensatory increase in food intake. Subchronic DA+NE reuptake inhibitor coadministration mimicked the effect of BUP on activity and temperature, but caused weight loss because daily food intake was not increased. The results of this study suggest that the mild weight loss effect of BUP in humans may be due to increased locomotion or heat production. More importantly, inhibition of DA+NE reuptake (with GBR+NIS) increased energy expenditure without a compensatory increase in food intake, supporting a role for novel combination catecholamine reuptake inhibitors in pharmacotherapy for obesity.

Although originally developed as an antidepressant, long-term bupropion (BUP) treatment was recently shown to cause 5-8% weight loss over placebo in clinical trials with obese adults. BUP's antidepressant properties probably stem from its ability to increase extracellular brain dopamine (DA) and norepinephrine (NE) levels by inhibiting their reuptake, although the mechanism of BUP-induced weight loss is unknown. Consequently, the acute effects of DA and NE reuptake inhibition on energy homeostasis were determined by measuring food intake and body weight in mice following peripheral (intraperitoneal (i.p.)) administration of either BUP, a selective DA (GBR12783), or a selective NE (nisoxetine (NIS)) reuptake inhibitor. BUP, GBR12783, and NIS all dose-dependently decreased acute food intake in fasted lean mice. The ability of BUP to decrease food intake was independent of its ability to cause a temporary increase in locomotor activity. The inhibitory effects of acute GBR12783 and NIS on short-term food intake were additive. Subchronic (via mini-osmotic pump) administration of GBR12783 and NIS produced a transient nonadditive effect on food intake, but produced an additive reduction in body weight (8-10%). Because obesity can affect catecholaminergic signaling, we determined the effects of i.p. BUP, GBR12783, and NIS on short-term food intake in obese mice. Acute BUP, GBR12783, and NIS dose-dependently reduced acute food intake, and the additive effect of GBR12783 and NIS on acute food intake was preserved in obese mice. These results demonstrate that combined DA and NE reuptake inhibition produces additive effects on energy balance in lean and obese mice on both standard and high-fat diet, providing a foundation for further research on the effects of BUP and similar compounds on energy balance in mice.

Despite high leptin levels, most obese humans and rodents lack responsiveness to its appetite-suppressing effects. We demonstrate that leptin modulates NPY/AgRP and alpha-MSH secretion from the ARH of lean mice. High-fat diet-induced obese (DIO) mice have normal ObRb levels and increased SOCS-3 levels, but leptin fails to modulate peptide secretion and any element of the leptin signaling cascade. Despite this leptin resistance, the melanocortin system downstream of the ARH in DIO mice is over-responsive to melanocortin agonists, probably due to upregulation of MC4R. Lastly, we show that by decreasing the fat content of the mouse's diet, leptin responsiveness of NPY/AgRP and POMC neurons recovered simultaneously, with mice regaining normal leptin sensitivity and glycemic control. These results highlight the physiological importance of leptin sensing in the melanocortin circuits and show that their loss of leptin sensing likely contributes to the pathology of leptin resistance.

In the rodent, arcuate nucleus of the hypothalamus (ARH)-derived neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons have efferent projections throughout the hypothalamus that do not fully mature until the second and third postnatal weeks. Since this process is likely completed by birth in primates we characterized the ontogeny of NPY and melanocortin systems in the fetal Japanese macaque during the late second (G100), early third (G130) and late third trimesters (G170). NPY mRNA was expressed in the ARH, paraventricular nucleus (PVH), and dorsomedial nucleus of the hypothalamus (DMH) as early as G100. ARH-derived NPY projections to the PVH were initiated at G100 but were limited and variable; however, there was a modest increase in density and number by G130. ARH-NPY/agouti-related peptide (AgRP) fiber projections to efferent target sites were completely developed by G170, but the density continued to increase in the postnatal period. In contrast to NPY/AgRP projections, alphaMSH fibers were minimal at G100 and G130 but were moderate at G170. This study also revealed several significant species differences between rodent and the nonhuman primate (NHP). There were few NPY/catecholamine projections to the PVH and ARH prior to birth, while projections were increased in the adult. A substantial proportion of the catecholamine fibers did not coexpress NPY. In addition, cocaine and amphetamine-related transcript (CART) and alpha-melanocyte stimulating hormone (alphaMSH) were not colocalized in fibers or cell bodies. As a consequence of the prenatal development of these neuropeptide systems in the NHP, the maternal environment may critically influence these circuits. Additionally, because differences exist in the neuroanatomy of NPY and melanocortin circuitry the regulation of these systems may be different in primates than in rodents.

Peptide YY(3-36) [PYY(3-36)] is a hormone that is released after meal ingestion that is currently being investigated for the treatment of obesity; however, there are conflicting reports of the effects of PYY(3-36) on energy balance in rodent models. To shed light on this controversy, we studied the effect of PYY(3-36) on food intake and body weight in a nonhuman primate. Intravenous PYY(3-36) infusions before a morning meal transiently suppressed the rate of food intake but did not suppress the evening meal or 24-h intake. Twice-daily or continuous intravenous PYY(3-36) infusions to supraphysiological levels (levels that exceeded normal physiological levels) again suppressed the rate of feeding for the morning but not the evening meal. Twice-daily intravenous PYY(3-36) infusions for 2 weeks significantly decreased body weight in all test animals (average weight loss 1.9%) without changing insulin response to glucose infusion. These results show that endogenous PYY(3-36) may alter morning but not evening meal intake, and supraphysiological doses are required for effective suppression of food intake.