Serotonin,Eating Behavior,and Fat Intake

There is an intimate relationship between nutritional intake (eating) and serotonin activity. Experimental manipulations (mainly neuropharmacological) of serotonin influence the pattern of eating behavior, subjective feelings of appetite motivation, and the response to nutritional challenges. Similarly, nutritional manipulations (food restriction, dieting, or altered nutrient supply) change the sensitivity of the serotonin network. Traditionally, serotonin has been linked to the macronutrient carbohydrate via the intermediary step of plasma amino acid ratios. However, it has also been demonstrated that 5-HT drugs will reduce energy intake and reverse body weight gain in rats exposed to weight increasing high fat diets. 5-HT drugs can also reduce food intake and block weight gain of rats on a high fat cafeteria diet. Some diet selection studies in rats indicate that the most prominent reduction of macronutrient intake is for fat. These data indicate that 5-HT activity can bring about a reduction in fat consumption. In turn, different types of dietary fat can alter brain 5-HT activity. In human studies the methodology of food choice experiments has often precluded the detection of an effect of 5-HT manipulation on fat intake. However, there is evidence that in obese and lean subjects some 5-HT drugs can readily reduce the intake of high fat foods. Data also suggest that 5-HT activation can lead to a selective avoidance of fat in the diet. These effects of 5-HT on the intake of dietary fat may involve a pre-absorptive mechanism and there is evidence that 5-HT is linked to cholecystokinin and enterostatin. These proposals have theoretical and practical implications and suggest possible strategies to intensify or advance fat-induced satiety signals.     

The effects of peripherally injected serotonin on feeding and locomotor activities in carp Cyprinus carpio L.

The influence of intraperitoneal (IP) and intramuscular (IM) injections of serotonin (5-hydroxytryptamine or 5-HT, 10 μg/g body weight) on a number of parameters of feeding behavior and locomotor activity in carp Cyprinus carpio L. has been investigated. It was shown that exogenous serotonin decreased various parameters of feeding and locomotor activities, and IM injections caused stronger inhibitory effect than IP injections. IP administration of this biogenic amine reduced the food intake in fishes of different age groups, induced an increase of the search reaction time (the latency to leave the starting chamber after its front wall was raised, or latency period for feeding of fish) in carp fingerlings in the experiments with “single” feeding. IM injections significantly lowered food intake of carp fingerlings in 1, 5 and 53 h, two other parameters—during all period of observation. In the experiments with “group” feeding food intake, duration of “group” feeding and total duration of feeding decreased during all period of observation after IM administration and in 1 h after IP injections only. Duration of “single” feeding and locomotor activity were changed less distinctly. The strongest effect of serotonin (up to 100%) was shown for duration of “group” feeding. It was supposed that inhibitory effects of exogenous serotonin on feeding and locomotor activities in carps were caused by its peripheral effects as well as by partial involving of central effect.     

Thee effect of food intake on the central monoaminergic system in the snail, Lymnaea stagnalis

We investigated the effect of food intake on the serotonin and dopamine levels of the CNS as well as on the spontaneous firing activity of the CGC in isolated preparations from starved, feeding and satiated animals. Furthermore we investigated the effects of 1 microM serotonin and/or dopamine and their mixture on the firing activity of the CGC. The HPLC assay of serotonin and dopamine showed that during food intake both the serotonin and dopamine levels of the CNS increased whereas in satiated animals their levels were not significantly more than the control levels. Recording from the CGC in isolated CNS preparation from starved, feeding or satiated animals showed that feeding increased the firing frequency of the CGC compared to the starved control. The application of 1 microM dopamine decreased the firing frequency whereas the application of 1 microM serotonin increased the firing frequency of the CGC. We conclude that during food intake the external and internal food stimuli increase the activity of the central monoaminergic system and also increase the levels of monoamines in the CNS. Furthermore, we also suggest that the increased dopamine and serotonin levels both affect the activity of the serotonergic neurons during the different phases of feeding.     

Comparison of the effects of neuropeptide Y and adrenergic transmitters on LH release and food intake in male rats

In view of the recent demonstrations that Neuropeptide Y (NPY) and adrenergic transmitters coexist in neurons of the rat brain, we have compared the effects of intraventricular (Ivt) injections of NPY and catecholamines on LH release and food intake in intact male rats. Of the three catecholamines, dopamine (DA), norepinephrine (NE) and epinephrine (E), only E (5.3 micrograms or 15.9 micrograms/rat) significantly stimulated LH release, although NE and E (5.3 micrograms/rat) were equally effective in eliciting food intake in satiated rats. Ivt administration of 10 micrograms NPY significantly stimulated LH release, whereas either lower (0.5 or 2 micrograms/rat) or higher (25 micrograms/rat) doses were ineffective. In contrast, NPY at doses of 0.5 - 10 micrograms/rat increased cumulative food intake in a dose-related fashion. These findings present preliminary evidence of the physiological correlates of the neuronal coexistence of adrenergic transmitters and NPY in the brain and raise the possibility that NPY may normally act either independently, in concert with or via adrenergic systems to evoke LH release and feeding responses in the rat.     

Preferences Predict Food Intake From 5 to 11 Years,but Not in Girls With Higher Weight Concerns,Dietary Restraint,and %Body Fat

Food preferences (FP) predict food intake in childhood; however, the predictive power of FP may decline among girls as weight concerns (WC) and dietary restraint (DR) increase during preadolescence. To examine longitudinal change in the preference‐intake (P‐I) relation and assess whether this relation weakens among non‐Hispanic white girls (n = 197) with a history of WC and DR from age 5 to 11. Girls' preferences for and intake (kcal) of 10 palatable snack foods were assessed biennially. Height, weight, percent body fat (%BF), WC, and DR were measured. Individual correlation coefficients were calculated per girl to capture within‐person P‐I correlations at each time of measurement. Overall, FP predicted girls' snack food calorie intakes between 5 and 11 years, but latent profile analysis (LPA) revealed three distinct patterns of change in P‐I correlations over time: “strong/stable” P‐I correlations were relatively high and became stronger with age; “increasing/later null” P‐I correlations were initially weak and became stronger between 5 and 9 years, but dropped to near 0 at 11 years; “initially weak/later strong” P‐I correlations were initially null and increased with age. Mixed models revealed that the “increasing/later null” group had greater increases in %BF, and higher WC, DR, and BMI percentiles from 5 to 11 years, compared to the other groups. In summary, FP predicted snack food calorie intake among most girls during childhood, but waned as a predictor of calorie intake at age 11 for a subset of girls with increasing %BF, and higher WC, DR, and BMIs.     

Serotonin and the search for the anatomical substrate of aggression

Abstract

All species of animals display aggression in order to obtain resources such as territories, mates, or food. Appropriate displays of aggression rely on the correct identification of a potential competitor, an evaluation of the environmental signals, and the physiological state of the animal. With a hard-wired circuitry involving fixed numbers of neurons, neuromodulators like serotonin offer adaptive flexibility in behavioral responses without changing the “hard-wiring”. In a recent report, we combined intersectional genetics, quantitative behavioral assays and morphological analyses to identify single serotonergic neurons that modulate the escalation of aggression. We found anatomical target areas within the brain where these neurons appear to form synaptic contacts with 5HT1A receptor-expressing neurons, and then confirmed the likelihood of those connections on a functional level. In this Extra View article, we offer an extended discussion of these recent findings and elaborate on how they can link a cellular and functional mapping of an aggression-regulating circuit at a single-cell resolution level.     

Involvement of CRF on the anorexic effect of GLP-1 in layer chicks

Glucagon-like peptide-1 (GLP-1) is recognized as an anorexic peptide in the brain of chicks. However, the mechanism underlying the inhibition of feeding has not been well studied. It is reported that GLP-1 activates neurons containing corticotrophin-releasing factor (CRF) in the brain of mammals. Since CRF is also an anorexic peptide, it is possible that the anorexic effect of GLP-1 is mediated by CRF in chicks. The present study was carried out to test this. First, we determined plasma corticosterone (CORT) concentrations after intracerebroventricular (ICV) injection of GLP-1 and found that this treatment increased CORT release in layer chicks. The CORT-releasing effect was partly attenuated by co-injection of astressin, a CRF receptor antagonist, demonstrating that GLP-1 stimulated CORT secretion by activation of CRF neurons. CRF neurons also appear to be involved in mediating the inhibition of food intake by GLP-1 because this effect was also partly attenuated by astressin. Furthermore, we demonstrated that the anorexic effect of GLP-1 was weaker in broiler than layer chicks. The present results suggest that the anorexic effect of GLP-1 might be mediated by CRF neurons in the chick brain and that the sensitivity of the inhibitory response to GLP-1 differs between chick strains.     

Drugs that enhance central serotoninergic transmission diminish elective carbohydrate consumption by rats.

We previously showed (Science 198:1178, 1977) that fenfluramine or fluoxetine, drugs thought to enhance serotoninergic transmission, selectively decrease the rat's consumption of carbohydrates, without affecting protein intake, when animals are given simultaneous access to diets differing in protein (5% vs 45%) and carbohydrate contents; in contrast, d-amphetamine lacks this selective effect. Present studies affirm this relationship using another serotoninergic drug, MK-212, and show that the suppression of carbohydrate intake occurs whether the test diets contain variable amounts of protein, or carbohydrates, or of both nutrients. Evidence is presented that rats given diet mixtures containing various proportions of carbohydrates have the ability to regulate their carbohydrate intakes (i.e., to choose to eat amounts of each diet that, taken together, will give them a desired proportion of carbohydrate), and that this ability is independent of whether or not the carbohydrate consumed has a sweet taste. It is proposed that serotoninergic neurons comprise part of a behavioral feedback loop, whereby the consumption of carbohydrate (which, by altering plasma amino acid patterns, accelerates serotonin synthesis in brain neurons) diminishes the rat's subsequent tendency to consume additional carbohydrates. Drugs that enhance central serotoninergic transmission can probably be substituted for dietry carbohydrate to activate this behavioral loop.     

Circulating GLP-1 and CCK-8 reduce food intake by capsaicin-insensitive, nonvagal mechanisms

Previous reports suggest that glucagon-like peptide (GLP-1), a peptide secreted from the distal small intestine, is an endocrine satiation signal. Nevertheless, there are conflicting reports regarding the site where circulating GLP-1 acts to reduce food intake. To test the hypothesis that vagal afferents are necessary for reduction of food intake by circulating GLP-1, we measured intake of 15% sucrose during intravenous GLP-1 infusion in intact, vagotomized, and capsaicin-treated rats. We also measured sucrose intake during intravenous infusion of cholecystokinin, a peptide known to reduce food intake via abdominal vagal afferents. We found that reduction of intake by GLP-1 was not diminished by capsaicin treatment or vagotomy. In fact, reduction of sucrose intake by our highest GLP-1 dose was enhanced in vagotomized and capsaicin-treated rats. Intravenous GLP-1 induced comparable increases of hindbrain c-Fos immunoreactivity in intact, capsaicin-treated, and vagotomized rats. Plasma concentrations of active GLP-1 in capsaicin-treated rats did not differ from those of controls during the intravenous infusions. Finally, capsaicin treatment was not associated with altered GLP-1R mRNA in the brain, but nodose ganglia GLP-1R mRNA was significantly reduced in capsaicin-treated rats. Although reduction of food intake by intraperitoneal cholecystokinin was abolished in vagotomized and capsaicin-treated rats, reduction of intake by intravenous cholecystokinin was only partially attenuated. These results indicate that vagal or capsaicin-sensitive neurons are not necessary for reduction of food intake by circulating (endocrine) GLP-1, or cholecystokinin. Vagal participation in satiation by these peptides may be limited to paracrine effects exerted near the sites of their secretion.     

Ghrelin acts in the central nervous system to stimulate gastric acid secretion

Ghrelin is a novel acylated peptide that functions in the regulation of growth hormone release and energy metabolism. It was isolated from rat stomach as an endogenous ligand for growth hormone secretagogue receptor. Ghrelin is also localized in the arcuate nucleus of rat hypothalamus. Intracerebroventricular (ICV) administration increases food intake and body weight. We examined the effect of ghrelin on gastric acid secretion in urethane-anesthetized rats and found that ICV administration of ghrelin increased gastric acid output in a dose-dependent manner. Vagotomy and administration of atropine abolished the gastric acid secretion induced by ghrelin. ICV administration of ghrelin also induced c-fos expression in the neurons of the nucleus of the solitary tract and the dorsomotor nucleus of the vagus, which are key sites in the central nervous system for regulation of gastric acid secretion. Our results suggest that ghrelin participates in the central regulation of gastric acid secretion by activating the vagus system.     

Stress-and Endotoxin-Induced Increases in Brain Tryptophan and Serotonin Metabolism Depend on Sympathetic Nervous System Activity

Stressful treatments and immune challenges have been shown previously to elevate brain concentrations of tryptophan. The role of the autonomic nervous system in this neurochemical change was investigated using pharmacological treatments that inhibit autonomic effects. Pretreatment with the ganglionic blocker chlorisondamine did not alter the normal increases in catecholamine metabolites, but prevented the increase in brain tryptophan normally observed after footshock or restraint, except when the duration of the footshock period was extended to 60 min. The footshock- and restraint-related increases in 5-hydroxyindoleacetic acid (5-HIAA) were also prevented by chlorisondamine. The increases in brain tryptophan caused by intraperitoneal injection of endotoxin or interleukin-1 (IL-1) were also prevented by chlorisondamine pretreatment. The footshock-induced increases in brain tryptophan and 5-HIAA were attenuated by the beta-adrenergic antagonist propranolol but not by the alpha-adrenergic antagonist phenoxybenzamine or the muscarinic cholinergic antagonist atropine. Thus the autonomic nervous system appears to be involved in the stress-related changes in brain tryptophan, and this effect is due to the sympathetic rather than the parasympathetic limb of the system. Moreover, the main effect of the sympathetic nervous system is exerted on beta- as opposed to alpha-adrenergic receptors. We conclude that activation of the sympathetic nervous system is responsible for the stress-related increases in brain tryptophan, probably by enabling increased brain tryptophan uptake. Endotoxin and IL-1 also elevate brain tryptophan, presumably by a similar mechanism. The increase in brain tryptophan appears to be necessary to sustain the increased serotonin catabolism to 5-HIAA that occurs in stressed animals, and which may reflect increased serotonin release.     

Estradiol acts in the medial preoptic area, arcuate nucleus, and dorsal raphe nucleus to reduce food intake in ovariectomized rats

Estradiol (E2) exerts an inhibitory effect on food intake in a variety of species. While compelling evidence indicates that central, rather than peripheral, estrogen receptors (ERs) mediate this effect, the exact brain regions involved have yet to be conclusively identified. In order to identify brain regions that are sufficient for E2's anorectic effect, food intake was monitored for 48 h following acute, unilateral, microinfusions of vehicle and two doses (0.25 and 2.5 μg) of a water-soluble form of E2 in multiple brain regions within the hypothalamus and midbrain of ovariectomized rats. Dose-related decreases in 24-h food intake were observed following E2 administration in the medial preoptic area (MPOA), arcuate nucleus (ARC), and dorsal raphe nucleus (DRN). Within the former two brain areas, the larger dose of E2 also decreased 4-h food intake. Food intake was not influenced, however, by similar E2 administration in the paraventricular nucleus, lateral hypothalamus, or ventromedial nucleus. These data suggest that E2-responsive neurons within the MPOA, ARC, and DRN participate in the estrogenic control of food intake and provide specific brain areas for future investigations of the cellular mechanism underlying estradiol's anorexigenic effect.     

Effects of naloxone on the secretion of prolactin and corticosterone induced by 5-hydroxytryptophan and a serotonergic agonist, mCPP

The effects of naloxone, an opiate “pure” receptor antagonist, on the release of prolactin and corticosterone in the rat were studied following the administration of the serotonin precursor 5-hydroxytryptophan or the serotonin receptor agonist (?) -$\text{m}$-chloropnehylpiperazine. Naloxone clearly antagonizes the release of prolactin induced by 5-hydroxytryptophan administered alone at a dosage of 50 mg/Kg/b.wt. or at dosage of 30 mg/Kg/b.wt. preceded 60 minutes before injection by the administration of the serotonin uptake blocker fluoxetine. The opiate antagonist does not modify the increase in blood level of prolactin induced by (?) ?$\text{m}$-chlorohenylpiperazine. Naloxone itself does not reduce the increase in plasma level of corticosterone induced by 5-hydroxytryptophan, 5-hydroxytryptophan +fluoxetine or (?)?$\text{m}$-chlorophenylpiperazine.The results suggest that endogenous opioids may be involved in the increase in serum level of prolactin induced by 5-hydroxytryptophan and also indicate the existence of different serotonergic neurotransmitter circuits capable of modulating the release of prolactin and corticosterone. A mutual interplay between serotonergic and opiate neurons may be involved in controlling the release of prolactin, but such an interplay does not seem to occur in the secretion of corticotrophin-releasing hormone.     

Nutritional correlates of the “lean season”: Effects of seasonality and frugivory on the nutritional ecology of diademed sifakas

Primate field studies often identify “lean seasons,” when preferred foods are scarce, and lower‐quality, abundant foods (fallback foods) are consumed. Here, we quantify the nutritional implications of these terms for two diademed sifaka groups (Propithecus diadema) in Madagascar, using detailed feeding observations and chemical analyses of foods. In particular, we sought to understand 1) how macronutrient and energy intakes vary seasonally, including whether these intakes respond in similar or divergent ways; 2) how the amount of food ingested varies seasonally (including whether changes in amount eaten may compensate for altered food quality); and 3) correlations between these variables and the degree of frugivory. In the lean season, sifakas shifted to non‐fruit foods (leaves and flowers), which tended to be high in protein while low in other macronutrients and energy, but the average composition of the most used foods in each season was similar. They also showed dramatic decreases in feeding time, food ingested, and consequently, daily intake of macronutrients and energy. The degree of frugivory in the daily diet was a strong positive predictor of feeding time, amount ingested and all macronutrient and energy intakes, though season had an independent effect. These results suggest that factors restricting how much food can be eaten (e.g., handling time, availability, or intrinsic characteristics like fiber and plant secondary metabolites) can be more important than the nutritional composition of foods themselves in determining nutritional outcomes—a finding with relevance for understanding seasonal changes in behavior, life history strategies, competitive regimes, and conservation planning. Am J Phys Anthropol 153:78–91, 2014. © 2013 Wiley Periodicals, Inc.     

Fructose and uric acid as drivers of a hyperactive foraging response: A clue to behavioral disorders associated with impulsivity or mania?

Several behavioral disorders, including attention deficit hyperactivity disorder (ADHD), bipolar disorder, and aggressive behaviors are linked with sugar intake and obesity. The reason(s) for this association has been unclear. Here we present a hypothesis supporting a role for fructose, a component of sugar and high fructose corn syrup (HFCS), and uric acid (a fructose metabolite), in increasing the risk for these behavioral disorders. Recent studies have shown that the reason fructose intake is strongly associated with development of metabolic syndrome is that fructose intake activates an evolutionary-based survival pathway that stimulates foraging behavior and the storage of energy as fat. While modest intake may aid animals that would like to store fat as a protective response from food shortage or starvation, we propose that high intake of sugar and HFCS causes a hyperactive foraging response that stimulates craving, impulsivity, risk taking and aggression that increases the risk for ADHD, bipolar disease and aggressive behavior. High glycemic carbohydrates and salty foods may also contribute as they can be converted to fructose in the body. Some studies suggest uric acid produced during fructose metabolism may mediate some of these effects. Chronic stimulation of the pathway could lead to desensitization of hedonic responses and induce depression. In conclusion, a hyperactive foraging response driven by high glycemic carbohydrates and sugars may contribute to affective disorders.     

Reduction of negative alliesthesia for sweet gustatory stimuli by cyproheptadine, a serotonin antagonist

Cyproheptadine (CH) is a serotonin antagonist that increases food intake and body weight. In order to elucidate its mechanism of action on the control of food intake, hunger ratings, pleasure-displeasure to sweet gustatory stimuli and negative alliesthesia induced by a 50 g glucose load were compared in 14 healthy subjects after they had received a placebo or 16 mg of CH. Cyproheptadine did not affect the hunger rating, nor the affective rating in fasted subjects, but it reduced significantly the negative alimentary alliesthesia induced by the glucose load. It was concluded that CH increases food intake more by reducing satiation than by increasing hunger. This is in line with the anti-serotoninergic properties of CH, and the action of serotonin on the control of food intake.     

Food reward, hyperphagia, and obesity

Given the unabated obesity problem, there is increasing appreciation of expressions like "my eyes are bigger than my stomach," and recent studies in rodents and humans suggest that dysregulated brain reward pathways may be contributing not only to drug addiction but also to increased intake of palatable foods and ultimately obesity. After describing recent progress in revealing the neural pathways and mechanisms underlying food reward and the attribution of incentive salience by internal state signals, we analyze the potentially circular relationship between palatable food intake, hyperphagia, and obesity. Are there preexisting individual differences in reward functions at an early age, and could they be responsible for development of obesity later in life? Does repeated exposure to palatable foods set off a cascade of sensitization as in drug and alcohol addiction? Are reward functions altered by secondary effects of the obese state, such as increased signaling through inflammatory, oxidative, and mitochondrial stress pathways? Answering these questions will significantly impact prevention and treatment of obesity and its ensuing comorbidities as well as eating disorders and drug and alcohol addiction.     

Synaptic and Extrasynaptic Secretion of Serotonin

Serotonin is a major modulator of behavior in vertebrates and invertebrates and deficiencies in the serotonergic system account for several behavioral disorders in humans.The small numbers of serotonergic central neurons of vertebrates and invertebrates produce their effects by use of two modes of secretion: from synaptic terminals, acting locally in hard wired circuits, and from extrasynaptic axonal and somatodendritic release sites in the absence of postsynaptic targets, producing paracrine effects.In this paper, we review the evidence of synaptic and extrasynaptic release of serotonin and the mechanisms underlying each secretion mode by combining evidence from vertebrates and invertebrates. Particular emphasis is given to somatic secretion of serotonin by central neurons.Most of the mechanisms of serotonin release have been elucidated in cultured synapses made by Retzius neurons from the central nervous system of the leech. Serotonin release from synaptic terminals occurs from clear and dense core vesicles at active zones upon depolarization. In general, synaptic serotonin release is similar to release of acetylcholine in the neuromuscular junction.The soma of Retzius neurons releases serotonin from clusters of dense core vesicles in the absence of active zones. This type of secretion is dependent of the stimulation frequency, on L-type calcium channel activation and on calcium-induced calcium release.The characteristics of somatic secretion of serotonin in Retzius neurons are similar to those of somatic secretion of dopamine and peptides by other neuron types. In general, somatic secretion by neurons is different from transmitter release from clear vesicles at synapses and similar to secretion by excitable endocrine cells.     

Differential effect of the 5-HTT gene-linked polymorphic region on emotional eating during stress exposure following tryptophan challenge

Stress and negative moods, which are thought to be partly mediated by reduced brain serotonin function, often increase emotional eating in dieting women (restrainers). Because the short (S) allele polymorphism in the serotonin transporter gene (5-HTTLPR) is associated with serotonin dysfunction, S allele compared to long (L) allele 5-HTTLPR genotypes may be more susceptible to stress-induced emotional eating. Consequently, serotonin challenge via tryptophan (TRP)-rich protein hydrolysate (TPH) may alleviate stress-induced emotional eating particularly in S/S allele carriers. We tested whether acute stress affects emotional eating in women with high or low dietary restraints depending on their 5-HTTLPR genotype and TPH intake. Nineteen female subjects who were homozygous for the short-allele 5-HTTLPR genotype (S'/S'=S/L(G), L(G)/L(G): restrainers vs. nonrestrainers) and 23 female subjects who were homozygous for the long-allele 5-HTTLPR genotype (L'/L'=L(A)/L(A): restrainers vs. nonrestrainers) were tested in a double-blind, placebo-controlled crossover study of stress-induced emotional eating following intake of TPH or a placebo. TPH intake significantly increased the plasma TRP/large neutral amino acid ratio (P<.0001) in the L'/L' group (70%) compared to the S'/S' group (30%). TPH reduced food intake in both groups, but in the L'/L' group, it also reduced stress-induced negative mood (P=.037) and the desire for sweet, high-fat foods (P=.011) regardless of dietary restraint. Conclusions: Since TPH caused a greater increase in the plasma TRP/large neutral amino acid ratio in the L'/L' group compared to S'/S' group, the exclusive beneficial effects of L'/L' genotype may be due to enhanced brain 5-HT function.     

Macronutrients and obesity: Revisiting the calories in,calories out framework

Recent clinical research has studied weight responses to varying diet composition, but the contribution of changes in macronutrient intake and physical activity to rising population weight remains controversial. Research on the economics of obesity typically assumes a “calories in, calories out” framework, but a weight production model separating caloric intake into carbohydrates, fat, and protein, has not been explored in an economic framework. To estimate the contributions of changes in macronutrient intake and physical activity to changes in population weight, we conducted dynamic time series and structural VAR analyses of U.S. data between 1974 and 2006 and a panel analysis of 164 countries between 2001 and 2010. Findings from all analyses suggest that increases in carbohydrates are most strongly and positively associated with increases in obesity prevalence even when controlling for changes in total caloric intake and occupation-related physical activity. Our structural VAR results suggest that, on the margin, a 1% increase in carbohydrates intake yields a 1.01 point increase in obesity prevalence over 5 years while an equal percent increase in fat intake decreases obesity prevalence by 0.24 points.