Competing paradigms of obesity pathogenesis: energy balance versus carbohydrate-insulin models.

The obesity pandemic continues unabated despite a persistent public health campaign to decrease energy intake ("eat less") and increase energy expenditure ("move more"). One explanation for this failure is that the current approach, based on the notion of energy balance, has not been adequately embraced by the public. Another possibility is that this approach rests on an erroneous paradigm. A new formulation of the energy balance model (EBM), like prior versions, considers overeating (energy intake > expenditure) the primary cause of obesity, incorporating an emphasis on "complex endocrine, metabolic, and nervous system signals" that control food intake below conscious level. This model attributes rising obesity prevalence to inexpensive, convenient, energy-dense, "ultra-processed" foods high in fat and sugar. An alternative view, the carbohydrate-insulin model (CIM), proposes that hormonal responses to highly processed carbohydrates shift energy partitioning toward deposition in adipose tissue, leaving fewer calories available for the body's metabolic needs. Thus, increasing adiposity causes overeating to compensate for the sequestered calories. Here, we highlight robust contrasts in how the EBM and CIM view obesity pathophysiology and consider deficiencies in the EBM that impede paradigm testing and refinement. Rectifying these deficiencies should assume priority, as a constructive paradigm clash is needed to resolve long-standing scientific controversies and inform the design of new models to guide prevention and treatment. Nevertheless, public health action need not await resolution of this debate, as both models target processed carbohydrates as major drivers of obesity.

The carbohydrate-insulin model: a physiological perspective on the obesity pandemic.

According to a commonly held view, the obesity pandemic is caused by overconsumption of modern, highly palatable, energy-dense processed foods, exacerbated by a sedentary lifestyle. However, obesity rates remain at historic highs, despite a persistent focus on eating less and moving more, as guided by the energy balance model (EBM). This public health failure may arise from a fundamental limitation of the EBM itself. Conceptualizing obesity as a disorder of energy balance restates a principle of physics without considering the biological mechanisms that promote weight gain. An alternative paradigm, the carbohydrate-insulin model (CIM), proposes a reversal of causal direction. According to the CIM, increasing fat deposition in the body-resulting from the hormonal responses to a high-glycemic-load diet-drives positive energy balance. The CIM provides a conceptual framework with testable hypotheses for how various modifiable factors influence energy balance and fat storage. Rigorous research is needed to compare the validity of these 2 models, which have substantially different implications for obesity management, and to generate new models that best encompass the evidence.

Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men: A secondary analysis of energy expenditure and physical activity.

BACKGROUND: A previously published pilot study assessed energy expenditure (EE) of participants with overweight and obesity after they were switched from a baseline high-carbohydrate diet (BD) to an isocaloric low-carbohydrate ketogenic diet (KD). EE measured using metabolic chambers increased transiently by what was considered a relatively small extent after the switch to the KD, whereas EE measured using doubly labeled water (EEDLW) increased to a greater degree after the response in the chambers had waned. Using a publicly available dataset, we examined the effect of housing conditions on the magnitude of the increase in EEDLW after the switch to the KD and the role of physical activity in that response. METHODS: The 14-day EEDLW measurement period included 4 days when subjects were confined to chambers instead of living in wards. To determine the effect on EEDLW only for the days subjects were living in the wards, we calculated non-chamber EE (EEnonchamber). To assess the role of physical activity in the response to the KD, we analyzed chamber and non-chamber accelerometer data for the BD and KD EEDLW measurement periods. RESULTS: In comparison with the increase in average 14-day EEDLW of 151 kcal/d ± 63 (P = 0.03) after the switch to the KD, EEnonchamber increased by 203 ± 89 kcal/d (P = 0.04) or 283 ± 116 kcal/d (P = 0.03) depending on the analytical approach. Hip accelerometer counts decreased significantly (P = 0.01) after the switch to the KD, whereas wrist and ankle accelerometer counts did not change. CONCLUSIONS: Switching from the BD to the KD substantially increased EEDLW, but apparently only on days subjects were living in the ward outside the metabolic chamber. Increased physical activity as measured by accelerometry did not appear to account for this effect.

Is there a relationship between dietary MSG and [corrected] obesity in animals or humans?

The sodium salt of glutamate (monosodium glutamate; MSG) imparts a savory/meaty taste to foods, and has been used as a flavoring agent for millennia. Past research on MSG/glutamate has evaluated its physiologic, metabolic and behavioral actions, and its safety. Ingested MSG has been found to be safe, and to produce no remarkable effects, except on taste. However, some recent epidemiologic and animal studies have associated MSG use with obesity and aberrations in fat metabolism. Reported effects are usually attributed to direct actions of ingested MSG in brain. As these observations conflict with past MSG research findings, a symposium was convened at the 13th International Congress on Amino Acids, Peptides and Proteins to discuss them. The principal conclusions were: (1) the proposed link between MSG intake and weight gain is likely explained by co-varying environmental factors (e.g., diet, physical activity) linked to the "nutrition transition" in developing Asian countries. (2) Controlled intervention studies adding MSG to the diet of animals and humans show no effect on body weight. (3) Hypotheses positing dietary MSG effects on body weight involve results from rodent MSG injection studies that link MSG to actions in brain not applicable to MSG ingestion studies. The fundamental reason is that glutamate is metabolically compartmentalized in the body, and generally does not passively cross biologic membranes. Hence, almost no ingested glutamate/MSG passes from gut into blood, and essentially none transits placenta from maternal to fetal circulation, or crosses the blood-brain barrier. Dietary MSG, therefore, does not gain access to brain. Overall, it appears that normal dietary MSG use is unlikely to influence energy intake, body weight or fat metabolism.

Food restriction, refeeding, and gastric fill fail to affect emesis in musk shrews.

Nausea and emesis are common side effects of gastrointestinal disease. Reports indicate that ghrelin and endocannabinoids, agents that stimulate appetite, also reduce emesis evoked by chemotherapy treatment, which suggests that stimulation of feeding inhibits the emetic system. In the following study we conducted a more direct test of this hypothesis by determining the impact of manipulating the motivation to eat on emesis, using food restriction and refeeding. Emesis was induced in musk shrews, a commonly used animal model for emesis research, using the cancer chemotherapy agent cisplatin (20 mg/kg ip), nicotine (2 mg/kg sc), or motion (1 Hz, horizontal, 4-cm displacement), because these treatments are known to target separate emetic pathways: gut vagal afferents, area postrema, and vestibular pathways, respectively. Twenty-four hours of food restriction was sufficient to stimulate food intake, and 1 h of refeeding filled the stomach. The results indicate that food restriction, refeeding, and gastric fill had no significant effects on the amount of emesis produced by any of the emetic treatments tested here. This suggests that, although activation of the emetic system might have prominent effects on food intake, neural controls for feeding behavior do not significantly affect the neural pathways for emesis. These results may have implications for how we treat patients who experience a constellation of side effects, including nausea and emesis, since stimulating appetite may not necessarily inhibit emetic pathways.

Frequency of coronary artery bypass grafting following implantation of a paclitaxel-eluting or a bare-metal stent into a single coronary artery.

Limited data are available on the relative effect of drug-eluting versus bare-metal stents on the requirement for subsequent coronary artery bypass grafting (CABG). The aim of this study was to evaluate the incidence and predictors of CABG after bare-metal and paclitaxel-eluting coronary stent implantation. A patient-level, pooled analysis was conducted of 2,736 patients from 3 double-blind, randomized trials comparing the slow-release paclitaxel-eluting Taxus stent with an otherwise identical bare-metal stent control in single de novo coronary lesions, with 5-year follow-up. The rate of target lesion revascularization by CABG (TLR-CABG) was reduced from 4.1% in patients with bare-metal stents to 1.4% in those with Taxus stents (p <0.001). The use of the Taxus stent was the strongest predictor of freedom from TLR-CABG on multivariate analysis (hazard ratio 0.33, p <0.001). Significant reductions in TLR-CABG with Taxus compared with bare-metal stents were seen in the treatment of left anterior descending artery lesions (6.1% vs 1.8%, p <0.001) and non-left anterior descending artery lesions (2.8% vs 1.3%, p = 0.037), in patients with diabetes (6.0% vs 1.0%, p <0.01), and in those without diabetes (3.5% vs 1.6%, p <0.01). In conclusion, referral to CABG is significantly less common after stenting single coronary lesions with Taxus compared with bare-metal stents. The relative reductions in TLR-CABG of 54% in patients without diabetes, 87% in patients with diabetes, 70% in left anterior descending artery lesions, and 54% in non-left anterior descending artery lesions with Taxus compared with bare-metal stents should be considered during stent selection.

Reduced capacity for fatty acid oxidation in rats with inherited susceptibility to diet-induced obesity.

High-fat, energy-dense diets promote weight gain and obesity in humans and other animals, but the mechanisms underlying such diet-induced obesity remain elusive. To determine whether a reduced capacity to oxidize fat is involved in the etiology of diet-induced obesity, we examined different measures of fatty acid oxidation in rats selectively bred for susceptibility (DIO) or resistance (DR) to dietary obesity before and after they were fed a high-fat diet and became obese. DIO rats eating a low-fat diet oxidized less dietary fatty acid in vivo and had lower levels of plasma ketone bodies during fasting compared with DR rats. Lean DIO rats fed a low-fat diet showed reduced liver messenger RNA expression of CD36, which transports fatty acids across cell membranes, and long-chain acyl-coenzyme A dehydrogenase (ACADL), which catalyzes the first step in the mitochondrial beta-oxidation of fatty acids. The deficit in CD36 and ACADL messenger RNA expression was also seen in obese DIO rats that had been eating a high-fat diet and, in addition, was accompanied by reduced expression of liver carnitine palmitoyl transferase I, the enzyme that mediates transport of long-chain fatty acids into mitochondria. No differences were found in the expression of liver enzymes involved in fat synthesis; however, in muscle, DIO rats fed the low-fat, but not high-fat, diet showed greater expression of diacylglycerol O-acyltransferase 1 and lipoprotein lipase than did DR rats. Expression of muscle enzymes involved in fatty acid oxidation was similar in the 2 groups. These findings provide a metabolic mechanism for the development of diet-induced obesity and thus suggest potential targets for intervention strategies to treat or prevent it.

Obesity and the hepatic control of feeding behavior.

Despite its well-established role in the control of food intake, the liver has not been a target for the development of drugs to modulate appetite and treat obesity. This paper provides an overview of the hepatic control of food intake and focuses in particular on how it may play a part in overeating and body weight gain. Signals from the liver that control feeding behavior are triggered in response to changes in liver energy status and are carried to the brain by vagal sensory neurons. Consumption of diets rich in fat and carbohydrate is a major contributing cause of overeating and obesity, and susceptibility to such diet-induced obesity is associated with a reduced capacity for fat oxidation. Inhibition of fatty acid oxidation in the liver stimulates food intake by decreasing liver ATP production, suggesting that low liver energy status may contribute to diet-induced overeating and obesity. These findings raise the possibility that liver energy production, the mechanisms that transduce changes in hepatic energy status into neural signals or hepatic vagal afferent activity may provide new targets for the development of drugs for appetite control and obesity.

Off-label use: an industry perspective on expanding use beyond approved indications.

The use of a medical device outside of its approved label is commonly referred to as "off-label use." Off-label use arises when physicians see the opportunity to leverage an approved therapy for an unmet patient need. This practice typically occurs on a case by case basis without clear documentation of indication, frequency, or outcomes. Sponsors have a responsibility to consider formal indication expansion depending on the actual use, how well the therapy fits the unmet need, product iteration cycles, adoption speed, resource demands, and the clinical risk to benefit ratio. This responsibility is particularly relevant for breakthrough technologies where adoption patterns can span a variety of uses. For Boston Scientific's drug-eluting stent program, a surveillance program was developed in collaboration with the FDA to compile information on practice patterns and safety outcomes for the TAXUS Express2 Paclitaxel-Eluting Coronary Stent System. The ARRIVE program has used a Web-based format to collect real-time data on TAXUS stent use. This >7,000 patient registry documents both on-label and off-label use and key safety measures for the TAXUS stent. This real-world registry has successfully provided a data-driven approach to BSC's product development strategy, including the initiation of formal label expansion programs. For complex or combination products, more innovative ways of capturing risk to benefit data are needed to define off-label use and to maximize the potential therapeutic utility as supported by safety data.

Thoracic cross-over pathways of the rat vagal trunks.

It is very difficult to study the independent contributions of the afferent and efferent pathways of the subdiaphragmatic vagus to physiology and behavior. Total subdiaphragmatic vagotomy can confound the interpretation of experimental results because it destroys both afferent and efferent vagal fibers. One approach to address this problem involves producing a total ablation of afferent (or efferent) vagal fibers while retaining half of the efferent (or afferent) vagal fibers by making a unilateral rhizotomy plus contralateral subdiaphragmatic vagotomy. However, the completeness of this afferent (or efferent) lesion is based on the assumption that there are no cross-over pathways within the thoracic cavity between the vagal trunks of the rat. To directly test for the presence of vagal cross-over pathways in the rat, we recorded the compound action potentials from the ventral and dorsal trunks of the subdiaphragmatic vagus following electrical stimulation of the left or right cervical vagi. C-fiber cross-over pathways comprised an average of 9% of the total nerve responses (range was 0 to 29%, n = 20). Direct application of the anesthetic bupivacaine to the vagus completely blocked the recorded signals. The vagal cross-over pathways were also demonstrated using capsaicin as a stimulus. These results indicate the presence of thoracic cross-over pathways between vagal trunks in the rat and demonstrate that for most animals it is not possible to produce a "complete" ablation of afferent (or efferent) components of the subdiaphragmatic vagus using unilateral rhizotomy combined with contralateral subdiaphragmatic vagotomy.

Pica--a model of nausea? Species differences in response to cisplatin.

Rats lack the emetic reflex but exhibit pica in response to stimuli that induce emesis in species with an emetic reflex, hence it has been proposed that pica may be analogous to emesis in species lacking the reflex. In the present study, we investigated whether pica was present in Suncus murinus (with an emetic reflex) as well as in rats and mice (without emetic reflex) to provide a further insight to the validity of pica as a model for nausea/vomiting. Cisplatin (6 mg/kg, i.p.) induced pica in rats, indicated by a significant increase in kaolin consumption at 24 h (but not 48 h) post-treatment whereas we failed to demonstrate this effect in mice (inbred or outbred strain, 6 or 20 mg/kg i.p.) and whilst cisplatin (20 mg/kg, i.p.) induced emesis in Suncus, kaolin intake was not significantly affected. Furthermore, cisplatin significantly increased the weight of gastric contents at 48 h post-injection in rats and mice indicating delayed gastric emptying whereas this effect was not present in Suncus. These results show that Suncus and two strains of mice, unlike rats, do not develop pica in response to cisplatin which suggests that the consumption of kaolin induced by cisplatin may not be associated with whether or not an emetic reflex is present. The differences in ingestive behaviour and gastric response between species with and without an emetic reflex in response to cisplatin treatment as well as the difference between mice and rats, is discussed in relation to the selection of models for the study of nausea and vomiting.

Potential energetic implications of emesis in the house musk shrew (Suncus murinus).

During the course of studies investigating novel anti-emetic therapies we serendipitously observed a previously unreported behaviour related to emesis in the house musk shrew. This behaviour consisted of spontaneous ingestion of vomit in about half of the animals (males and females) in which emesis was induced by either nicotine (4 mg kg-1 sc.) or horizontal motion (1 Hz, 4 cm, 10 min). Analysis of vomit samples and gastric contents revealed that in a "typical" individual the gastric contents would be voided by as few as 3 vomits. Energetic calculations of the metabolisable energy of food, gastric contents, vomit and field metabolic rate (FMR) predict that a male weighing 60 g would lose 17.3% of its hourly energy requirement for FMR if it vomited once. A 40 g female, however, would experience an hourly energy loss of approximately 22.8%. The possible energetic consequences and resulting ecological implications of this unusual behaviour are discussed.

Phenotype-based treatment of dietary obesity: differential effects of fenofibrate in obesity-prone and obesity-resistant rats.

High-fat diets (HFDs) promote hyperphagia and adiposity in animals and human beings. To test the hypothesis that limitations on fat oxidation underlie this propensity for diet-induced obesity, rats were treated with fenofibrate, which enhances fat oxidation mainly in liver by inducing expression of enzymes and proliferation of organelles involved in fatty acid oxidation. Male Sprague-Dawley rats were fed a HFD (42% fat calorie) for 2 weeks. Rats ranked in the top and bottom thirds for weight gain during this feeding period were designated as obesity prone (OP) and obesity resistant (OR), respectively. Fenofibrate was added to the HFD (0.025% wt/wt) for half of the OP and OR rats. During the next 10 days, fenofibrate treatment significantly (P<.05) reduced food intake, weight gain, feed efficiency, and adiposity in OP rats to levels seen in control OR rats, but had no such effects in OR rats. Fenofibrate treatment increased whole-body fatty acid oxidation, and in liver, the expression of carnitine palmitoyl transferase I only in OP rats, but enhanced expression of acyl-CoA oxidase in both OP and OR rats. Restricting food intake of OP rats to levels seen in rats given fenofibrate similarly reduced weight gain but had little effect on weight of fat pads. Treatment with the daily dosage of fenofibrate given as a bolus did not produce a conditioned flavor aversion. These results suggest that enhancement of mitochondrial fatty acid oxidation in liver may be an effective phenotype-based treatment strategy for dietary obesity.

Differential effects on gastrointestinal and hepatic vagal afferent fibers in the rat by the anti-cancer agent cisplatin.

Cisplatin, a cancer chemotherapy agent, like many toxins, produces emesis and nausea. Abdominal vagotomy, or treatment with 5-HT3 receptor antagonists, blocks cisplatin-induced emesis, which suggests that it produces (albeit indirectly) activation of 5-HT3 receptors on vagal afferent fibers. Cisplatin induces a large release of intestinal 5-hydroxytryptamine (5-HT) that enters the hepatic portal vein, which may activate vagal afferent fibers in the portal vein or liver to induce emesis or other side effects of treatment (e.g., reduced food intake). This study was conducted to assess the effects of cisplatin on gastrointestinal and portal vein/liver vagal afferent fibers by recording the neurophysiological responses of the common hepatic branch (CHB) of the vagus in the rat. The CHB contains vagal afferent fibers that innervate the gastrointestinal (GI) tract, portal vein, and liver. Cisplatin (10 mg/kg; jugular vein, j.v.) produced an increase in multi-unit CHB activity and this effect was blocked by a 5-HT3-receptor antagonist (Y-25130, 0.8 mg, j.v.). Cutting the gastroduodenal branch (GDB), a sub-branch of the CHB that contains GI afferent fibers, resulted in a complete suppression of the multi-unit CHB discharge produced by cisplatin treatment. Single units that were cisplatin sensitive had their activity reduced by either 5-HT3 receptor antagonist treatment or cutting the GDB. Conversely, cisplatin insensitive units were not affected by 5-HT3-antagonism or GDB ablation. The present results indicate that cisplatin activates GI vagal afferent fibers via 5-HT3 receptors but does not affect portal vein/liver vagal afferent fibers, which indicates that intestinal but not hepatic afferent fibers are involved in the toxic effects of cisplatin.

Etomoxir, a fatty acid oxidation inhibitor, increases food intake and reduces hepatic energy status in rats.

Etomoxir, an inhibitor of fatty acid oxidation, increases food intake and reported hunger in humans. Work with animal models suggests that other inhibitors of fatty acid oxidation stimulate feeding behavior by acting on the liver. In the following study, we assessed whether etomoxir would increase food intake in rats and to what degree the effects of etomoxir on feeding were associated with changes in hepatic energy status. The effects of etomoxir on hepatic energy status were assessed by measuring liver ATP, ADP, phosphorylation potential, and glycogen content. Blood glucose, free fatty acids, and ketone bodies were also measured to determine the availability of circulating fuels following etomoxir treatment. Etomoxir and methyl palmoxirate (MP; another inhibitor of fatty acid oxidation) increased food intake. Etomoxir, like MP, also reduced hepatic ATP/ADP ratio and phosphorylation potential. In combination with 2,5-anhydro-D-mannitol (an analogue of fructose that produces an increase in feeding by action on the liver), etomoxir synergistically increased food intake and reduced hepatic ATP/ADP ratio. In summary, etomoxir increased food intake and decreased hepatic energy status in the rat. This suggests that etomoxir stimulates feeding by action on the liver.