Using genetic variation to disentangle the complex relationship between food intake and health outcomes

Diet is considered as one of the most important modifiable factors influencing human health, but efforts to identify foods or dietary patterns associated with health outcomes often suffer from biases, confounding, and reverse causation. Applying Mendelian randomization in this context may provide evidence to strengthen causality in nutrition research. To this end, we first identified 283 genetic markers associated with dietary intake in 445,779 UK Biobank participants. We then converted these associations into direct genetic effects on food exposures by adjusting them for effects mediated via other traits. The SNPs which did not show evidence of mediation were then used for MR, assessing the association between genetically predicted food choices and other risk factors, health outcomes. We show that using all associated SNPs without omitting those which show evidence of mediation, leads to biases in downstream analyses (genetic correlations, causal inference), similar to those present in observational studies. However, MR analyses using SNPs which have only a direct effect on the exposure on food exposures provided unequivocal evidence of causal associations between specific eating patterns and obesity, blood lipid status, and several other risk factors and health outcomes.     

Cross-talk between adipose and gastric leptins for the control of food intake and energy metabolism

The understanding of the regulation of food intake has become increasingly complex. More than 20 hormones, both orexigenic and anorexigenic, have been identified. After crossing the blood-brain barrier, they reach their main site of action located in several hypothalamic areas and interact to balance satiety and hunger.One of the most significant advances in this matter has been the discovery of leptin. This hormone plays fundamental roles in the control of appetite and in regulating energy expenditure. In accordance with the lipostatic theory stated by Kennedy in 1953, leptin was originally discovered in white adipose tissue. Its expression by other tissues was later established. Among them, the gastric mucosa has been shown to secrete large amounts of leptin. Both the adipose and the gastric tissues share similar characteristics in the synthesis and storage of leptin in granules, in the formation of a complex with the soluble receptor and a secretion modulated by hormones and energy substrates. However while adipose tissue secretes leptin in a slow constitutive endocrine way, the gastric mucosa releases leptin in a rapid regulated exocrine fashion into the gastric juice.Exocrine-secreted leptin survives the extreme hydrolytic conditions of the gastric juice and reach the duodenal lumen in an intact active form. Scrutiny into transport mechanisms revealed that a significant amount of the exocrine leptin crosses the intestinal wall by active transcytosis. Leptin receptors, expressed on the luminal and basal membrane of intestinal epithelial cells, are involved in the control of nutrient absorption by enterocytes, mucus secretion by goblet cells and motility, among other processes, and this control is indeed different depending upon luminal or basal stimulus. Gastric leptin after transcytosis reaches the central nervous system, to control food intake.Studies using the Caco-2, the human intestinal cell line, in vitro allowed analysis of the mechanisms of leptin actions on the intestinal mucosa, identification of the mechanisms of leptin transcytosis and understanding the modulation of leptin receptors by nutrients and hormones.Exocrine-secreted gastric leptin thus participates in a physiological axis independent in terms of time and regulation from that of adipose tissue to rapidly control food intake and nutrient absorption. Adipocytes and gastric epithelial cells are two cell types the metabolism of which is closely linked to food intake and energy storage. The coordinated secretion of adipose and gastric leptins ensures proper management of food processing and energy storage.     

Hypothalamic neuronal histamine mediates the thyrotropin-releasing hormone-induced suppression of food intake

We examined the involvement of thyrotropin-releasing hormone (TRH) and TRH type 1 and 2 receptors (TRH-R1 and TRH-R2, respectively) in the regulation of hypothalamic neuronal histamine. Infusion of 100 nmol TRH into the rat third cerebroventricle (3vt) significantly decreased food intake (p < 0.05) compared to controls infused with phosphate- buffered saline. This TRH-induced suppression of food intake was attenuated partially in histamine-depleted rats pre-treated with alpha-fluoromethylhistidine (a specific suicide inhibitor of histidine decarboxylase) and in mice with targeted disruption of histamine H1 receptors. Infusion of TRH into the 3vt increased histamine turnover as assessed by pargyline-induced accumulation of tele-methylhistamine (t-MH, a major metabolite of neuronal histamine in the brain) in the tuberomammillary nucleus (TMN), the paraventricular nucleus, and the ventromedial hypothalamic nucleus in rats. In addition, TRH-induced decrease of food intake and increase of histamine turnover were in a dose-dependent manner. Microinfusion of TRH into the TMN increased t-MH content, histidine decarboxylase (HDC) activity and expression of HDC mRNA in the TMN. Immunohistochemical analysis revealed that TRH-R2, but not TRH-R1, was expressed within the cell bodies of histaminergic neurons in the TMN of rats. These results indicate that hypothalamic neuronal histamine mediates the TRH-induced suppression of feeding behavior.     

Modeling the relationship between body weight and energy intake: A molecular diffusion-based approach

ABSTRACT: BACKGROUND: Body weight is at least partly controlled by the choices made by a human in response to external stimuli. Changes in body weight are mainly caused by energy intake. By analyzing the mechanisms involved in food intake, we considered that molecular diffusion plays an important role in body weight changes. We propose a model based on Fick's second law of diffusion to simulate the relationship between energy intake and body weight. RESULTS: This model was applied to food intake and body weight data recorded in humans; the model showed a good fit to the experimental data. This model was also effective in predicting future body weight. CONCLUSIONS: In conclusion, this model based on molecular diffusion provides a new insight into the body weight mechanisms.     

Ghrelin and the regulation of food intake and energy balance

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is synthesized principally in the stomach and is released in response to acute and chronic changes in nutritional state. In addition to having a powerful effect on the secretion of growth hormone, ghrelin stimulates food intake and transduces signals to hypothalamic regulatory nuclei that control energy homeostasis. Thus, it is interesting to note that the stomach may play an important role in not only digestion but also pituitary growth hormone release and central feeding regulation. We summarize recent findings on the integration of ghrelin into neuroendocrine networks that regulate food intake and energy balance.     

Peptide signals regulating food intake and energy homeostasis

The adiposity hormone leptin has been shown to decrease food intake and body weight by acting on neuropeptide circuits in the hypothalamus. However, it is not clear how this primary hypothalamic action of leptin is translated into a change in food intake. We hypothesize that the behavioral effect of leptin ultimately involves the integration of neuronal responses in the forebrain with those in the nucleus tractus solitarius in the caudal brainstem, where ingestive behavior signals are received from the gastrointestinal system and the blood. One example is the peptide cholecystokinin, which is released from the gut following ingestion of a meal and acts via vagal afferent nerve fibers to activate medial nucleus tractus solitarius neurons and thereby decrease meal size. While it is established that leptin acts in the arcuate nucleus in the hypothalamus to stimulate anorexigenic neurons that inhibit food intake while simulataneously inhibiting orexigenic neurons that increase food intake, the mechanisms linking these effects with regions of the caudal brainstem that integrate cues related to meal termination are unclear. Based on an increasing body of supportive data, we hypothesize that this integration involves a pathway comprising descending projections from neurons from the paraventricular nucleus to neurons within the nucleus tractus solitarius that are activated by meal-related satiety factors. Leptin's anorexic effect comprises primarily decreased meal size, and at subthreshold doses for eliciting an effect on food intake, leptin intensifies the satiety response to circulating cholecystokinin. The location of neurons subserving the effects of intracerebroventricular administration of leptin and intraperitoneal injection of cholecystokinin on food intake has been identified by analysis of Fos expression. These studies reveal a distribution that includes the paraventricular nucleus and regions within the caudal brainstem, with the medial nucleus tractus solitarius having the most pronounced Fos expression in response to leptin and cholecystokinin, and support the hypothesis that the long-term adiposity signal leptin and the short-term satiety signal cholecystokinin act in concert to maintain body weight homeostasis.     

Opioids in the regulation of food intake and energy expenditure

This paper and the following four papers summarize a symposium on the role of opioids in regulation of feeding, body weight, and energy expenditure. The central sites of opioid action are discussed, as is opioid activity in invertebrates, large animals, and humans. This paper provides a historical review of developments in the field from the early concepts of an endogenous opioid system to the current understanding of multiple receptor types and their interaction in regulating ingestive behavior. Opioids from all three opioid families may stimulate food intake, and some evidence exists that opioids may stimulate energy expenditure. Eating and drinking behavior is very complex and involves a number of components. Our understanding of the role of opioids in this process is shallow, and future research must be designed carefully to evaluate individual components of ingestive behavior.     

The relationship between forage cell wall content and voluntary food intake in mammalian herbivores

• 1 It is generally assumed that animals compensate for a declining diet quality with increasing food intake. Differences in the response to decreasing forage quality in herbivores have been postulated particularly between cattle (ruminants) and horses (hindgut fermenters). However, empirical tests for both assumptions in herbivorous mammals are rare.
• 2 We collected data on voluntary food intake in mammals on forage‐only diets and related this to dietary neutral detergent fibre (NDF) content, assuming a nonlinear correlation between these measurements. Generally, the paucity of corresponding data is striking.
• 3 Elephants and pandas showed very high food intakes that appeared unrelated to dietary fibre content. Only in small rodents, and possibly in rabbits, was an increase in food intake on forages of higher NDF content evident. In particular, other large herbivores, including horses, followed patterns of decreasing intake with increasing forage NDF, also observed in domestic cattle or sheep.
• 4 For large herbivores, empirical data therefore do not – so far – support the notion that intake is increased in response to declining diet quality. However, data are in accord with the assumption that most large herbivores have an anticipatory strategy of acquiring body reserves when high‐quality forage is available, and reducing food intake (and potentially metabolic losses) when only low‐quality forage is available.
• 5 Intake studies in which the influence of digestive strategy on food intake capacity is tested should be designed as long‐term studies that outlast an anticipatory strategy and force animals to ingest as much as possible.
• 6 We suggest that a colonic separation mechanism coupled with coprophagy, in order to minimize metabolic faecal losses, is necessary below a body size threshold where an anticipatory strategy (living off body reserves, migration) is not feasible. Future studies aimed at investigating fine‐scale differences, for example between equids and bovids, should focus on non‐domesticated species.

     

Leptin: a possible link between food intake, energy expenditure, and reproductive function

Several regulatory substances participate in the regulation of both food intake/energy metabolism and reproduction in mammals. Most of these neuropeptides originate and act in the central nervous system, mainly at specific hypothalamic areas. Leptin represents a signal integrating all these functions, but originating from the periphery (adipose tissue) and carrying information mainly to central structures. Observations in rodent models of leptin deficiency have suggested that leptin participates in the control of reproduction, in conjunction with that of food intake and energy expenditure. Indeed, leptin administration resulted in the restoration of normal body weight, food intake, and fertility in the ob mouse, lacking circulating leptin. Specific targets of leptin in the hypothalamus are neurons expressing neuropeptide Y, proopiomelanocortin and gonadotropin-releasing hormone, but the presence of leptin receptors in peripheral reproductive structures suggests that leptin might also act at these sites. Human obesity is often associated with reproductive disturbances. The situation in humans is more complex than in the animal models of leptin deficit and the presence of leptin resistance in these subjects is suggested. In conclusion, leptin fits many requirements for a molecule linking the regulation of energy balance and the control of reproduction.     

Heparanase affects food intake and regulates energy balance in mice

Mutation of the melanocortin-receptor 4 (MC4R) is the most frequent cause of severe obesity in humans. Binding of agouti-related peptide (AgRP) to MC4R involves the co-receptor syndecan-3, a heparan sulfate proteoglycan. The proteoglycan can be structurally modified by the enzyme heparanase. Here we tested the hypothesis that heparanase plays a role in food intake behaviour and energy balance regulation by analysing body weight, body composition and food intake in genetically modified mice that either lack or overexpress heparanase. We also assessed food intake and body weight following acute central intracerebroventricular administration of heparanase; such treatment reduced food intake in wildtype mice, an effect that was abolished in mice lacking MC4R. By contrast, heparanase knockout mice on a high-fat diet showed increased food intake and maturity-onset obesity, with up to a 40% increase in body fat. Mice overexpressing heparanase displayed essentially the opposite phenotypes, with a reduced fat mass. These results implicate heparanase in energy balance control via the central melanocortin system. Our data indicate that heparanase acts as a negative modulator of AgRP signaling at MC4R, through cleavage of heparan sulfate chains presumably linked to syndecan-3.     

Flock size and habitat-dependent food and energy intake of foraging Goldfinches

Summary During the breeding season Goldfinches (Carduelis carduelis L.) feed on milky ripe seeds of about 20 food plants. Individual Goldfinches joining a flock reduce the time spent vigilant with increasing flock size. Therefore birds feeding in flocks get an increased intake of kernels per time unit. This was measured for five different food plants (Dactylis glomerata (Gramineae), Knautia arvensis (Dipsacaceae), Senecio vulgaris, Taraxacum officinale, Tragopogon pratensis (Compositae)). In large-sized flocks, birds fed up to 2.3 times more kernels, than when feeding solitarily. In addition, visibility in the vegetation leads to a further increase of kernel intake. Thus feeding under good conditions as in recently mown areas, can raise kernel intake to the seven fold per time unit as compared to solitary feeding. The maximum ingestion rate of kernels was 98 per min which implies a head up-and-down movement every 0.6 s. The calculated energy intake of birds per time unit is lowest in Senecio and highest in Tragopogon. Thus the birds, when feeding on Tragopogon in larger flocks, can gain an energy intake 16 times higher than that reached when feeding on Senecio, despite of a higher kernel intake rate. The energy intake individual Goldfinches gain at the particular plant species is markedly increased with flock sizes up to eight birds, with larger flocks the intake increases only slightly.     

Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance

Macroautophagy is a lysosomal degradative pathway that maintains cellular homeostasis by turning over cellular components. Here we demonstrate a role for autophagy in hypothalamic agouti-related peptide (AgRP) neurons in the regulation of food intake and energy balance. We show that starvation-induced hypothalamic autophagy mobilizes neuron-intrinsic lipids to generate endogenous free fatty acids, which in turn regulate AgRP levels. The functional consequences of inhibiting autophagy are the failure to upregulate AgRP in response to starvation, and constitutive increases in hypothalamic levels of pro-opiomelanocortin and its cleavage product α-melanocyte-stimulating hormone that typically contribute to a lean phenotype. We propose a conceptual framework for considering how autophagy-regulated lipid metabolism within hypothalamic neurons may modulate neuropeptide levels to have immediate effects on food intake, as well as long-term effects on energy homeostasis. Regulation of hypothalamic autophagy could become an effective intervention in conditions such as obesity and the metabolic syndrome.     

Metabolic inhibitors synergistically decrease hepatic energy status and increase food intake

Previous studies indicate that administration of the metabolic inhibitor, 2,5-anhydro-D-mannitol (2,5-AM) or methyl palmoxirate (MP), induces feeding behavior in rats by lowering hepatic energy status. Combined treatment with these agents synergistically increases food intake. The present study was designed to investigate whether combined treatment also has a synergistic effect on hepatic energy status. Rats treated with both inhibitors increased feeding behavior compared with the controls, whereas those treated with 2, 5-AM or MP alone did not. Although 2,5-AM alone lowered hepatic ATP content regardless of MP treatment, only the combination resulted in decreases in hepatic ATP/ADP ratio and phosphorylation potential. MP treatment did not affect the uptake of 2,5-AM into liver. These results suggest that a reduction in hepatic energy status is the common triggering signal for eating behavior induced by 2,5-AM and MP and provide additional evidence for an integrated metabolic control of food intake.     

Divergence of melanocortin pathways in the control of food intake and energy expenditure

Activation of melanocortin-4-receptors (MC4Rs) reduces body fat stores by decreasing food intake and increasing energy expenditure. MC4Rs are expressed in multiple CNS sites, any number of which could mediate these effects. To identify the functionally relevant sites of MC4R expression, we generated a loxP-modified, null Mc4r allele (loxTB Mc4r) that can be reactivated by Cre-recombinase. Mice homozygous for the loxTB Mc4r allele do not express MC4Rs and are markedly obese. Restoration of MC4R expression in the paraventricular hypothalamus (PVH) and a subpopulation of amygdala neurons, using Sim1-Cre transgenic mice, prevented 60% of the obesity. Of note, increased food intake, typical of Mc4r null mice, was completely rescued while reduced energy expenditure was unaffected. These findings demonstrate that MC4Rs in the PVH and/or the amygdala control food intake but that MC4Rs elsewhere control energy expenditure. Disassociation of food intake and energy expenditure reveals unexpected divergence in melanocortin pathways controlling energy balance.     

Male voice pitch mediates the relationship between objective and perceived formidability

Acoustic signals function in intrasexual mating competition in a wide variety of species, including humans. The low voice pitch of human males has been proposed to represent an honest signal of formidability. Although voice pitch in men affects perceptions of size and dominance, it is relatively weakly associated with objective measures of formidability such as body size and strength. As a result, some authors have argued that low male voice pitch is not a valid signal of formidability but is deceptive and salient only because it hijacks a tendency to perceive lower frequency sounds as emanating from larger sources. In this paper, we consider theoretical and empirical issues associated with this perceptual exploitation hypothesis and ask whether male voice pitch transmits information about formidability. We utilize mediation models to investigate whether male voice pitch is an honest signal of formidability in data collected from university students in the U.S. (n = 231 male speakers, 565 male raters) and Canada (n = 74 male speakers, 108 female raters, 65 male raters). In both data sets, male voice pitch mediated the relationship between objective (measured by height) and perceived formidability. Collectively, these results indicate that men’s voice pitch transmits information about formidability from signaler to receiver.     

Landscape context mediates the relationship between plant functional traits and decomposition

Plant and Soil - It has been well demonstrated that several interacting endogenous and exogenous factors influence decomposition. However, teasing apart the direct and indirect effects of these...     

Muscle strength mediates the relationship between mitochondrial energetics and walking performance

Skeletal muscle mitochondrial oxidative capacity declines with age and negatively affects walking performance, but the mechanism for this association is not fully clear. We tested the hypothesis that impaired oxidative capacity affects muscle performance and, through this mechanism, has a negative effect on walking speed. Muscle mitochondrial oxidative capacity was measured by in vivo phosphorus magnetic resonance spectroscopy as the postexercise phosphocreatine resynthesis rate, k_PCr, in 326 participants (154 men), aged 24–97 years (mean 71), in the Baltimore Longitudinal Study of Aging. Muscle strength and quality were determined by knee extension isokinetic strength, and the ratio of knee extension strength to thigh muscle cross‐sectional area derived from computed topography, respectively. Four walking tasks were evaluated: a usual pace over 6 m and for 150 s, and a rapid pace over 6 m and 400 m. In multivariate linear regression analyses, k_PCr was associated with muscle strength (β = 0.140, P = 0.007) and muscle quality (β = 0.127, P = 0.022), independent of age, sex, height, and weight; muscle strength was also a significant independent correlate of walking speed (P < 0.02 for all tasks) and in a formal mediation analysis significantly attenuated the association between k_PCr and three of four walking tasks (18–29% reduction in β for k_PCr). This is the first demonstration in human adults that mitochondrial function affects muscle strength and that inefficiency in muscle bioenergetics partially accounts for differences in mobility through this mechanism.