Nutrient-sensing Signaling Pathways Research Articles

Promotion of Successful Weight Management in Overweight and Obese Veterans (POWER-VET): Trial Design and Methods

BackgroundAlmost 75% of US adults are overweight or obese. Though intentional weight loss of as little as 3% improves physical functioning and reduces cardiometabolic risk, most adults are unsuccessful at long-term weight maintenance. Our hypothesis is that intermittent fasting (IF: short periods of intense energy restriction) will reduce weight regain. IF may combat obesity due to its effects on nutrient-sensing signaling pathways and circadian rhythm. The objective of this randomized clinical trial is to test the effectiveness of an intensive body weight management program with and without IF. MethodsIn the Promotion of Successful Weight Management in Overweight and Obese Veterans (POWER-VET) trial (NCT04131647), 154 middle-aged and older adults (50–75 years) who are overweight and obese (BMI: 25–40 kg/m2) and seen at either a Baltimore, MD or San Antonio, TX Veterans Affairs Medical Center will be enrolled. Participants will undergo 12 weeks of weight loss (including a low-calorie heart healthy (HH) diet and exercise). Following weight loss, participants will be randomly assigned to one of two 24-week weight maintenance (WM) interventions: WM alone (continuation of HH diet and exercise) or WM + IF. The primary aim is to determine the effect of WM + IF compared to WM alone on body weight maintenance after intentional weight loss. DiscussionDetermining effective, translatable strategies that minimize weight regain following successful weight loss holds public health relevance. This POWER-VET trial introduces an innovative practice of IF to prevent weight regain after clinically significant weight reduction and could provide evidence-based recommendations to promote this type of intervention in middle aged and older adults.

Interference in the nutrient-sensing and inflammatory signaling pathways by renal autophagy activation in mice with late stage diabetic nephropathy.

Disturbance in metabolism and inflammation are the main causes of kidney injury in patients with late stage diabetic nephropathy (DN). Here, we explored whether autophagy was activated in mice with late stage DN and whether it was associated with disturbance in metabolism and inflammation. In total, mice were divided into the control group (db/m) and DN group (db/db). Mice were raised for 7months, and their biochemical indices were measured. Subsequently, their kidneys were collected to detect autophagy and the related nutrient-sensing and inflammatory signaling pathways in late stage DN. The expression levels of autophagy markers LC3-I and LC3-II were significantly increased in mice with late stage DN, whereas that of autophagy flux marker P62 was significantly decreased, indicating activation of autophagy. Concurrently, mechanistic target of rapamycin was highly expressed as a cellular nutrient-sensing and energy regulator in mice with late stage DN. Additionally, the expression levels of markers of nutrient-sensing signaling pathways adenosine monophosphate-activated protein kinase (AMPK) were increased markedly in mice with late stage DN. Additionally, the expression levels of the marker of nutrient-sensing signaling pathways silent information regulator T1 (SIRT1), the marker of inflammatory signaling pathways high mobility group box protein 1 (HMGB1), and interferon regulatory factor 3 (IRF3) were significantly increased in mice with late stage DN. The findings of our study indicate that autophagy activation in late stage DN may interfere with nutrient-sensing and inflammatory signaling pathways involving AMPK, SIRT1, HMGB1, and IRF3.

Dietary choline can partially spare methionine to improve the feeds utilization and immune response in juvenile largemouth bass (Micropterus salmoides): Based on phenotypic response to gene expression

Present study was conducted to explore the interrelationship between dietary methionine and choline in feed formulations for largemouth bass (Micropterus salmoides). Four isonitrogenous (51.0%) and isolipidic (14.0%) diets were formulated supplemented or not supplemented with methionine and choline: NC diet (basic diet), Met diet (basic diet supplemented with methionine), Cho diet (basic diet supplemented with choline) and PC diet (basic diet supplemented with methionine and choline). Fish with an initial body weight of 8.01 ± 0.08 g were fed with each diet for 8 weeks. Significant interactions were found between dietary methionine and choline on growth performance, plasma nutrient concentration, genes expression level of nutrient sensing signaling pathways, nutrient metabolism and immune response. Dietary methionine addition had great effects on improving weight gain rate (WGR), specific growth rate (SGR) and Feed efficiency ratio (FER), while choline supplementation only increased FER (P＜0.05). Both added methionine and choline had higher WGR, SGR and FER than the other groups (P＜0.05). Moreover, compared with NC group, PC, Met and Cho groups also activated growth hormone/insulin-like growth factor (GH-IGF), mammalian target of rapamycin (mTOR) pathway and shut down amino acid response (AAR) pathway to further enhanced glucose, lipid synthesis (P＜0.05). Dietary choline and methionine were similar in regulating the activity of signaling pathways (P > 0.05). Supplemented both together had the most significant effect on promoting nutrient accumulation and improving feed efficiency (P＜0.05). Furthermore, methionine and choline addition also enhanced the gene expression level of key regulators in immune response. Combined supplementation could improve this effect than the individual supplementation to a certain degree. Therefore, when methionine met the requirement of largemouth bass, choline supplementation could further raise the utilization of methionine and partially spare methionine efficiently. This study provided a more reasonably method for using choline to improve growth and feed utilization which could maximize growth and avoid the toxic effect of excessive methionine addition in diets.

Nutrient sensing signaling and metabolic responses in shrimp Litopenaeus vannamei under acute ammonia stress

Ammonia is the primary environmental factor affecting the growth and health of crustaceans. It would induce oxidative stress and metabolic disorders. Extra amount of energy was demanded to maintain the physiological functions under ammonia stress. However, limited information was available on its effects on the main nutrient metabolism, as well as the nutrient sensing signaling pathways. In the present study, shrimp Litopenaeus vannamei were exposed to acute ammonia stress and injected with amino acid solution. The results showed that acute ammonia exposure resulted in lower free amino acid levels in hemolymph, incomplete activation of the mechanistic target of rapamycin (mTOR) signaling and cascaded less protein synthesis in muscle. It induced autophagy and activated the AMP-activated protein kinase (AMPK) pathway. Meanwhile, ammonia exposure enhanced glycolysis and lipogenesis, but inhibited lipolysis. The results characterized the integrated metabolic responses and nutrient signaling to ammonia stress. It provides critical clues to understand the growth performance and physiological responses in shrimp under ammonia stress.

Antibody development to identify components of IIS and mTOR signaling pathways in lepidopteran species, a set of non-model insects.

Nutritional stress impacts many insect species that have differing reproductive strategies and life histories, yet it is unclear how nutrient-sensing signaling pathways mediate tissue-specific responses to changes in dietary input. In Drosophila melanogaster , insulin/insulin-like growth factor (IIS) and mTOR-mediated signaling within adipocytes regulates oogenesis. To facilitate comparative study of nutrient-sensing pathway activity in the fat body, we developed antibodies to assess IIS (anti-FOXO) and mTOR signaling (anti-TOR) across three nymphalid species (Lepidoptera). By optimizing whole-mount fat body immunostaining, we find FOXO nuclear enrichment in adult adipocytes, like that observed in Drosophila . Additionally, we show a previously uncharacterized TOR localization pattern in the fat body.

Transcriptome analysis reveals the effects of dietary lipid level on growth performance and immune response in golden pompano (Trachinotus ovatus)

Present study was conducted to accurately evaluate the optimal dietary lipid level in golden pompano (Trachinotus ovatus) diets combining phenotypic responses and transcriptomics analysis. Fish with initial body weight 27.65 g ± 0.17 g were fed diets with six lipid levels (9.13%, 10.59%, 12.12%, 14.98%, 16.25%, 19.26%), respectively. Results showed that dietary lipid levels significantly altered the weight gain rate, specific growth rate protein efficiency ratio and reached the maximum when fish fed diet with 12.12% lipid. Proximate composition analysis indicated that body nutrients content were significantly improved by dietary lipid levels. Moreover, total glucose, triglycerides and high-density lipoprotein were also elevated by dietary lipid level. Transcriptomic analysis suggested that muscle growth regulation, hormone response, nutrient metabolism and immune response were more sensitive to dietary lipid levels. Further analyzed mechanisms, data demonstrated that dietary lipid levels could through nutrient sensing signaling pathways to regulate lipid metabolism. Meanwhile, Diet 3 (lipid level: 12.12%) had lower level mRNA expression of the key regulators in immune responses and antioxidant defense. Either too lower or too higher lipid in diet could trigger oxidative stress and immune responses. In conclusion, according to broken-line regression on WGR and SGR, the optimal lipid level for golden pompano were 11.28% and 11.20%, respectively. Present study provided the optimal requirement of dietary lipid level based on a comprehensive method.

Muscle Nutritive Metabolism Changes after Dietary Fishmeal Replaced by Cottonseed Meal in Golden Pompano (Trachinotus ovatus).

Our previous study demonstrated that based on growth performance and feed utilization, cottonseed meal (CSM) could substitute 20% fishmeal (FM) without adverse effect on golden pompano (Trachinotus ovatus). Muscle deposition was also an important indicator to evaluate the efficiency of alternative protein sources. Therefore, the present study was conducted to explore the changes of physiobiochemical and nutrient metabolism in muscle after FM replaced by CSM. Four isonitrogenous and isolipidic experimental diets (42.5% crude protein, 14.0% crude lipid) were formulated to replace 0% (CSM0 diet), 20% (CSM20 diet), 40% (CSM40 diet), and 60% (CSM60 diet) of FM with CSM. Juvenile fish (24.8 ± 0.02 g) were fed each diet for 6 weeks. The results presented, which, compared with the CSM0 diet, CSM20 and CSM40 diets, had no effect on changing the muscle proximate composition and free essential amino acid (EAA) concentration. For glycolipid metabolism, the CSM20 diet did not change the mRNA expression of hexokinase (hk), glucose transport protein 4 (glut4), glucagon-like peptide 1 receptor (glp-1r), while over 20% replacement impaired glucose metabolism. However, CSM20 and CSM40 diets had no effect on altering lipid metabolism. Mechanistically, compared with the CSM0 diet, the CSM20 diet did not change muscle nutritive metabolism through keeping the activities of the nutrient sensing signaling pathways stable. Higher replacement would break this balance and lead to muscle nutritive metabolism disorders. Based on the results, CSM could substitute 20–40% FM without affecting the muscle nutritive deposition. All data supplemented the powerful support for our previous conclusion that CSM could successfully replace 20% FM based on growth performance.

Tracing copper utilization by kinase signal transduction pathways: Implications for cancer cell processes

Akin to organic nutrients, such as oxygen, lipids, amino acids, and carbohydrates, the transition metal copper (Cu) is an essential dietary nutrient for normal physiology and development. Decades of research highlight the physiological and disease associated consequences of disrupting homeostatic mechanisms that ensure proper Cu acquisition, storage, and distribution to Cu‐dependent enzymes. However, phenotypes associated with alterations in Cu availability cannot be fully explained by the limited number of enzymes that traditionally harness the redox potential of Cu as a catalytic cofactor. Recent discoveries in Cu biology have revealed direct Cu binding at non‐catalytic sites within signaling molecules that modulate cell proliferation via the protein kinases MEK1/2, lipid metabolism via the phosphodiesterase PDE3B, and nutrient recycling via the autophagic kinases ULK1/2. The emergence of this new paradigm in nutrient sensing and protein regulation has established that Cu is a critical mediator of intracellular signaling, provided evidence for the existence of molecular mechanisms for sensing changes in Cu abundance, and expanded the contribution of Cu to cellular processes necessary for adaptation to nutrient scarcity. Our presentation will focus on the intersections between Cu homeostasis, nutrient signaling, and metabolism by examining the interplay between mechanisms of Cu‐sensing necessary for cellular energy homeostasis and evaluating the necessity of Cu for metabolic flexibility under nutrient and oxygen stress. We will present novel findings on Cu‐controlled autophagy‐lysosomal biogenesis and function, and interconnectivity between mitochondrial Cu transport and cytosolic nutrient sensing signaling pathways necessary for metabolism. These studies increase our fundamental knowledge of the molecular and cellular features of Cu‐dependent enzymes and cellular processes and enable therapeutic targeting of Cu‐dependent disease vulnerabilities.

Intermittent and periodic fasting, longevity and disease.

Intermittent and periodic fasting (IF and PF, respectively) are emerging as safe strategies to affect longevity and healthspan by acting on cellular aging and disease risk factors, while causing no or minor side effects. IF lasting from 12 to 48 hours and repeated every 1 to 7 days and PF lasting 2 to 7 days and repeated once per month or less have the potential to prevent and treat disease, but their effect on cellular aging and the molecular mechanisms involved are only beginning to be unraveled. Here, we describe the different fasting methods and their effect on longevity in organisms ranging from yeast to humans, linking them to the major nutrient-sensing signaling pathways and focusing on the benefits of the fasting and the refeeding periods. We also discuss both the therapeutic potential and side effects of IF and PF with a focus on cancer, autoimmunity, neurodegeneration and metabolic and cardiovascular disease.

Coordinated control of adiposity and growth by anti-anabolic kinase ERK7.

Energy storage and growth are coordinated in response to nutrient status of animals. How nutrient‐regulated signaling pathways control these processes in vivo remains insufficiently understood. Here, we establish an atypical MAP kinase, ERK7, as an inhibitor of adiposity and growth in Drosophila. ERK7 mutant larvae display elevated triacylglycerol (TAG) stores and accelerated growth rate, while overexpressed ERK7 is sufficient to inhibit lipid storage and growth. ERK7 expression is elevated upon fasting and ERK7 mutant larvae display impaired survival during nutrient deprivation. ERK7 acts in the fat body, the insect counterpart of liver and adipose tissue, where it controls the subcellular localization of chromatin‐binding protein PWP1, a growth‐promoting downstream effector of mTOR. PWP1 maintains the expression of sugarbabe, encoding a lipogenic Gli‐similar family transcription factor. Both PWP1 and Sugarbabe are necessary for the increased growth and adiposity phenotypes of ERK7 loss‐of‐function animals. In conclusion, ERK7 is an anti‐anabolic kinase that inhibits lipid storage and growth while promoting survival on fasting conditions.

Global analysis of LARP1 translation targets reveals tunable and dynamic features of 5′ TOP motifs

Terminal oligopyrimidine (TOP) motifs are sequences at the 5' ends of mRNAs that link their translation to the mTOR Complex 1 (mTORC1) nutrient-sensing signaling pathway. They are commonly regarded as discrete elements that reside on ∼100 mRNAs that mostly encode translation factors. However, the full spectrum of TOP sequences and their prevalence throughout the transcriptome remain unclear, primarily because of uncertainty over the mechanism that detects them. Here, we globally analyzed translation targets of La-related protein 1 (LARP1), an RNA-binding protein and mTORC1 effector that has been shown to repress TOP mRNA translation in a few specific cases. We establish that LARP1 is the primary translation regulator of mRNAs with classical TOP motifs genome-wide, and also that these motifs are extreme instances of a broader continuum of regulatory sequences. We identify the features of TOP sequences that determine their potency and quantify these as a metric that accurately predicts mTORC1/LARP1 regulation called a TOPscore. Analysis of TOPscores across the transcriptomes of 16 mammalian tissues defines a constitutive "core" set of TOP mRNAs, but also identifies tissue-specific TOP mRNAs produced via alternative transcription initiation sites. These results establish the central role of LARP1 in TOP mRNA regulation on a transcriptome scale and show how it connects mTORC1 to a tunable and dynamic program of gene expression that is tailored to specific biological contexts.

NAD+ Metabolism and Regulation: Lessons From Yeast.

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite involved in various cellular processes. The cellular NAD+ pool is maintained by three biosynthesis pathways, which are largely conserved from bacteria to human. NAD+ metabolism is an emerging therapeutic target for several human disorders including diabetes, cancer, and neuron degeneration. Factors regulating NAD+ homeostasis have remained incompletely understood due to the dynamic nature and complexity of NAD+ metabolism. Recent studies using the genetically tractable budding yeast Saccharomyces cerevisiae have identified novel NAD+ homeostasis factors. These findings help provide a molecular basis for how may NAD+ and NAD+ homeostasis factors contribute to the maintenance and regulation of cellular function. Here we summarize major NAD+ biosynthesis pathways, selected cellular processes that closely connect with and contribute to NAD+ homeostasis, and regulation of NAD+ metabolism by nutrient-sensing signaling pathways. We also extend the discussions to include possible implications of NAD+ homeostasis factors in human disorders. Understanding the cross-regulation and interconnections of NAD+ precursors and associated cellular pathways will help elucidate the mechanisms of the complex regulation of NAD+ homeostasis. These studies may also contribute to the development of effective NAD+-based therapeutic strategies specific for different types of NAD+ deficiency related disorders.

Exposure of Pancreatic β-Cells to Excess Glucose Results in Bimodal Activation of mTORC1 and mTOR-Dependent Metabolic Acceleration.

SummaryChronic exposure of pancreatic β-cells to excess glucose can lead to metabolic acceleration and loss of stimulus-secretion coupling. Here, we examined how exposure to excess glucose (defined here as concentrations above 5 mM) affects mTORC1 signaling and the metabolism of β-cells. Acute exposure to excess glucose stimulated glycolysis-dependent mTORC1 signaling, without changes in the PI3K or AMPK pathways. Prolonged exposure to excess glucose led to hyperactivation of mTORC1 and metabolic acceleration, characterized by higher basal respiration and maximal respiratory capacity, increased energy demand, and enhanced flux through mitochondrial pyruvate metabolism. Inhibition of pyruvate transport to the mitochondria decelerated the metabolism of β-cells chronically exposed to excess glucose and re-established glucose-dependent mTORC1 signaling, disrupting a positive feedback loop for mTORC1 hyperactivation. mTOR inhibition had positive and negative impacts on various metabolic pathways and insulin secretion, demonstrating a role for mTOR signaling in the long-term metabolic adaptation of β-cells to excess glucose.

Nutrient Sensing, Signaling and Ageing: The Role of IGF-1 and mTOR in Ageing and Age-Related Disease.

Nutrient signaling throughinsulin/IGF-1 was the first pathway demonstrated to regulate ageing and age-related disease in model organisms. Pharmacological or dietary interventions targeting nutrient signaling pathways have been shown to robustly attenuate ageing in many organisms. Caloric restriction, the most widely studied longevity promoting intervention, works through multiple nutrient signaling pathways, while inhibition of mTOR through treatment with rapamycin reproducibly delays ageing and disease through specific inhibition of the mTOR complexes. Although the benefits of reduced insulin/IGF-1 in lifespan and health are well documented in model organisms, defining the precise role of the IGF-1 in human ageing and age-related disease has proven more difficult. Association studies provide some insight but also reveal paradoxes. Low serum IGF-1 predicts longevity, but IGF-1 decreases with age and IGF-1 therapy benefits some of age-related pathologies. Circulating IGF-1 has been associated both positively and negatively with risk of age-related diseases in humans, and in some cases both activation and inhibition of IGF-1 signaling have provided benefit in animal models of the same diseases. Interventions designed modulate the nutrient sensing signaling pathways positively or negatively are already available for clinical use, highlighting the need for a clear understanding of the role of nutrient signaling in ageing and age-related disease. This chapter examines data from model organisms and human genetic association studies, with a special emphasis on IGF-1 and mTOR, and discusses potential models for resolving the paradoxes surrounding IGF-1 data.

Regulation of reproduction and longevity by nutrient-sensing pathways.

Nutrients are necessary for life, as they are a crucial requirement for biological processes including reproduction, somatic growth, and tissue maintenance. Therefore, signaling systems involved in detecting and interpreting nutrient or energy levels-most notably, the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway, mechanistic target of rapamycin (mTOR), and adenosine monophosphate-activated protein kinase (AMPK)-play important roles in regulating physiological decisions to reproduce, grow, and age. In this review, we discuss the connections between reproductive senescence and somatic aging and give an overview of the involvement of nutrient-sensing pathways in controlling both reproductive function and lifespan. Although the molecular mechanisms that affect these processes can be influenced by distinct tissue-, temporal-, and pathway-specific signaling events, the progression of reproductive aging and somatic aging is systemically coordinated by integrated nutrient-sensing signaling pathways regulating somatic tissue maintenance in conjunction with reproductive capacity.

Placental Responses to Changes in the Maternal Environment Determine Fetal Growth

Placental responses to maternal perturbations are complex and remain poorly understood. Altered maternal environment during pregnancy such as hypoxia, stress, obesity, diabetes, toxins, altered nutrition, inflammation, and reduced utero-placental blood flow may influence fetal development, which can predispose to diseases later in life. The placenta being a metabolically active tissue responds to these perturbations by regulating the fetal supply of nutrients and oxygen and secretion of hormones into the maternal and fetal circulation. We have proposed that placental nutrient sensing integrates maternal and fetal nutritional cues with information from intrinsic nutrient sensing signaling pathways to balance fetal demand with the ability of the mother to support pregnancy by regulating maternal physiology, placental growth, and placental nutrient transport. Emerging evidence suggests that the nutrient-sensing signaling pathway mechanistic target of rapamycin (mTOR) plays a central role in this process. Thus, placental nutrient sensing plays a critical role in modulating maternal–fetal resource allocation, thereby affecting fetal growth and the life-long health of the fetus.

The update on transcriptional regulation of autophagy in normal and pathologic cells: A novel therapeutic target.

Autophagy is a genetically programmed, evolutionarily conserved catabolic process that occurs in response to stress. While short-lived proteins are degraded via the ubiquitin/proteasome pathway in higher eukaryotes, autophagy refers to intracellular pathway for development, differentiation, survival, and homeostasis through the lysosomal-dependent machinery, which regulates the synthesis, degradation, and recycling of long-lived proteins and even whole cytoplasmic organelles. The newly discovery shows that autophagy plays an important role in recycling nutrients upon starvation and maintaining cellular energy homeostasis. Recent basic and clinical investigations further demonstrate that autophagic abnormalities have been considered underlying reasons for lots of human diseases, including liver disease, cardiovascular and cerebrovascular diseases, neurodegenerative diseases, neoplastic diseases, and cancers. Pharmacological modulation of autophagy might point to possible therapeutic strategies for combating a broad range of diseases. Regrettably, although the mechanisms underlying the regulation of autophagy have long been attracted extensive concern of numerous scholars and its acute regulation by nutrient-sensing signaling pathways is well described, the overview on longer-term transcriptional regulation of autophagy is still filled with confusion. This review summarizes current knowledge on transcriptional regulation of autophagy and expands our horizons on the autophagy repertoire. On the other hand, it also offers a glimpse into different strategies that have been used in experimental models to counteract excessive pathological autophagy via transcriptional regulation mechanism in the prevention and treatment of disease.

Transgenerational inheritance of diet-induced genome rearrangements in Drosophila.

Ribosomal RNA gene (rDNA) copy number variation modulates heterochromatin formation and influences the expression of a large fraction of the Drosophila ge-nome. This discovery, along with the link between rDNA, aging, and disease, high-lights the importance of understanding how natural rDNA copy number variation arises. Pursuing the relationship between rDNA expression and stability, we have discovered that increased dietary yeast concentration, emulating periods of dietary excess during life, results in somatic rDNA instability and copy number reduction. Modulation of Insulin/TOR signaling produces similar results, indicating a role for known nutrient sensing signaling pathways in this process. Furthermore, adults fed elevated dietary yeast concentrations produce offspring with fewer rDNA copies demonstrating that these effects also occur in the germline, and are transgenera-tionally heritable. This finding explains one source of natural rDNA copy number variation revealing a clear long-term consequence of diet.

Nutrient-sensing nuclear receptors coordinate autophagy.

Autophagy is an evolutionally conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis1–3. Its acute regulation by nutrient sensing signaling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors PPARα and FXR are activated in the fasted or fed liver, respectively4,5. Here we show that both regulate hepatic autophagy. Pharmacologic activation of PPARα reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARα knockout (PPARα−/−) mice, which are partially defective in the induction of autophagy by fasting. Pharmacologic activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (FXR−/−) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARα and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status.

The role of placental nutrient sensing in maternal-fetal resource allocation.

The placenta mediates maternal-fetal exchange and has historically been regarded as a passive conduit for nutrients. However, emerging evidence suggests that the placenta actively responds to nutritional and metabolic signals from the mother and the fetus. We propose that the placenta integrates a multitude of maternal and fetal nutritional cues with information from intrinsic nutrient-sensing signaling pathways to match fetal demand with maternal supply by regulating maternal physiology, placental growth, and nutrient transport. This process, which we have called placental nutrient sensing, ensures optimal allocation of resources between the mother and the fetus to maximize the chances for propagation of parental genes without jeopardizing maternal health. We suggest that these mechanisms have evolved because of the evolutionary pressures of maternal undernutrition, which result in decreased placental growth and down-regulation of nutrient transporters, thereby limiting fetal growth to ensure maternal survival. These regulatory loops may also function in response to maternal overnutrition, leading to increased placental growth and nutrient transport in cases of maternal obesity or gestational diabetes. Thus, placental nutrient sensing modulates maternal-fetal resource allocation to increase the likelihood of reproductive success. This model implies that the placenta plays a critical role in mediating fetal programming and determining lifelong health.