Nutritional Signals Research Articles

Honeybee queen mandibular pheromone induces a starvation response in Drosophila melanogaster

Eusocial insect societies are defined by the reproductive division of labour, a social structure that is generally enforced by the reproductive dominant(s) or ‘queen(s)’. Reproductive dominance is maintained through behavioural dominance or production of queen pheromones, or a mixture of both.Queen mandibular pheromone (QMP) is a queen pheromone produced by queen honeybees (Apis mellifera) which represses reproduction in worker honeybees. How QMP acts to repress worker reproduction, the mechanisms by which this repression is induced, and how it has evolved this activity, remain poorly understood. Surprisingly, QMP is capable of repressing reproduction in non-target arthropods.Here we show that in Drosophila melanogaster QMP treatment mimics the starvation response, disrupting reproduction. QMP exposure induces an increase in food consumption and activation of checkpoints in the ovary that reduce fecundity and depresses insulin signalling. The magnitude of these effects is indistinguishable between QMP-treated and starved individuals. As QMP triggers a starvation response in an insect diverged from honeybees, we propose that QMP originally evolved by co-opting nutrition signalling pathways to regulate reproduction.

The Circadian Clock, Nutritional Signals and Reproduction: A Close Relationship.

The circadian rhythm, which is necessary for reproduction, is controlled by clock genes. In the mouse uterus, the oscillation of the circadian clock gene has been observed. The transcription of the core clock gene period (Per) and cryptochrome (Cry) is activated by the heterodimer of the transcription factor circadian locomotor output cycles kaput (Clock) and brain and muscle Arnt-like protein-1 (Bmal1). By binding to E-box sequences in the promoters of Per1/2 and Cry1/2 genes, the CLOCK-BMAL1 heterodimer promotes the transcription of these genes. Per1/2 and Cry1/2 form a complex with the Clock/Bmal1 heterodimer and inactivate its transcriptional activities. Endometrial BMAL1 expression levels are lower in human recurrent-miscarriage sufferers. Additionally, it was shown that the presence of BMAL1-depleted decidual cells prevents trophoblast invasion, highlighting the importance of the endometrial clock throughout pregnancy. It is widely known that hormone synthesis is disturbed and sterility develops in Bmal1-deficient mice. Recently, we discovered that animals with uterus-specific Bmal1 loss also had poor placental development, and these mice also had intrauterine fetal death. Furthermore, it was shown that time-restricted feeding controlled the uterine clock's circadian rhythm. The uterine clock system may be a possibility for pregnancy complications, according to these results. We summarize the most recent research on the close connection between the circadian clock and reproduction in this review.

Nutritional and tissue-specific regulation of cytochrome P450 CYP711A MAX1 homologues and strigolactone biosynthesis in wheat.

Strigolactones (SLs) are a class of phytohormones regulating branching/tillering, and their biosynthesis has been associated with nutritional signals and plant adaptation to nutrient-limiting conditions. The enzymes in the SL biosynthetic pathway downstream of carlactone are of interest as they are responsible for structural diversity in SLs, particularly cytochrome P450 CYP711A subfamily members, such as MORE AXILLARY GROWTH1 (MAX1) in Arabidopsis. We identified 13 MAX1 homologues in wheat, clustering in four clades and five homoeologous subgroups. The utilization of RNA-sequencing data revealed a distinct expression pattern of MAX1 homologues in above- and below-ground tissues, providing insights into the distinct roles of MAX1 homologues in wheat. In addition, a transcriptional analysis showed that SL biosynthetic genes were systematically regulated by nitrogen supply. Nitrogen limitation led to larger transcriptional changes in the basal nodes than phosphorus limitation, which was consistent with the observed tillering suppression, as wheat showed higher sensitivity to nitrogen. The opposite was observed in roots, with phosphorus limitation leading to stronger induction of most SL biosynthetic genes compared with nitrogen limitation. The observed tissue-specific regulation of SL biosynthetic genes in response to nutritional signals is likely to reflect the dual role of SLs as rhizosphere signals and branching inhibitors.

The Role of Nutrients and Nutritional Signals in the Pathogenesis of Vibrio cholerae.

Vibrio cholerae, the agent of cholera, is a natural inhabitant of aquatic environments. Over the past decades, the importance of specific nutrients and micronutrients in the environmental survival, host colonization, and pathogenesis of this species has become increasingly clear. For instance, V. cholerae has evolved ingenious mechanisms that allow the bacterium to colonize and establish a niche in the intestine of human hosts, where it competes with commensals (gut microbiota) and other pathogenic bacteria for available nutrients. Here, we discuss the carbon and energy sources utilized by V. cholerae and what is known about the role of nutrition in V. cholerae colonization. We examine how nutritional signals affect virulence gene regulation and how interactions with intestinal commensal species can affect intestinal colonization.

Peptide transport in Bacillus subtilis - structure and specificity in the extracellular solute binding proteins OppA and DppE.

Peptide transporters play important nutritional and cell signalling roles in Bacillus subtilis, which are pronounced during stationary phase adaptations and development. Three high-affinity ATP-binding cassette (ABC) family transporters are involved in peptide uptake - the oligopeptide permease (Opp), another peptide permease (App) and a less well-characterized dipeptide permease (Dpp). Here we report crystal structures of the extracellular substrate binding proteins, OppA and DppE, which serve the Opp and Dpp systems, respectively. The structure of OppA was determined in complex with endogenous peptides, modelled as Ser-Asn-Ser-Ser, and with the sporulation-promoting peptide Ser-Arg-Asn-Val-Thr, which bind with K d values of 0.4 and 2 µM, respectively, as measured by isothermal titration calorimetry. Differential scanning fluorescence experiments with a wider panel of ligands showed that OppA has highest affinity for tetra- and penta-peptides. The structure of DppE revealed the unexpected presence of a murein tripeptide (MTP) ligand, l-Ala-d-Glu-meso-DAP, in the peptide binding groove. The mode of MTP binding in DppE is different to that observed in the murein peptide binding protein, MppA, from Escherichia coli, suggesting independent evolution of these proteins from an OppA-like precursor. The presence of MTP in DppE points to a role for Dpp in the uptake and recycling of cell wall peptides, a conclusion that is supported by analysis of the genomic context of dpp, which revealed adjacent genes encoding enzymes involved in muropeptide catabolism in a gene organization that is widely conserved in Firmicutes.

Crosstalk between Nutrition, Insulin, Juvenile Hormone, and Ecdysteroid Signaling in the Classical Insect Model, Rhodnius prolixus

The rigorous balance of endocrine signals that control insect reproductive physiology is crucial for the success of egg production. Rhodnius prolixus, a blood-feeding insect and main vector of Chagas disease, has been used over the last century as a model to unravel aspects of insect metabolism and physiology. Our recent work has shown that nutrition, insulin signaling, and two main types of insect lipophilic hormones, juvenile hormone (JH) and ecdysteroids, are essential for successful reproduction in R. prolixus; however, the interplay behind these endocrine signals has not been established. We used a combination of hormone treatments, gene expression analyses, hormone measurements, and ex vivo experiments using the corpus allatum or the ovary, to investigate how the interaction of these endocrine signals might define the hormone environment for egg production. The results show that after a blood meal, circulating JH levels increase, a process mainly driven through insulin and allatoregulatory neuropeptides. In turn, JH feeds back to provide some control over its own biosynthesis by regulating the expression of critical biosynthetic enzymes in the corpus allatum. Interestingly, insulin also stimulates the synthesis and release of ecdysteroids from the ovary. This study highlights the complex network of endocrine signals that, together, coordinate a successful reproductive cycle.

Lifespan extension in female mice by early, transient exposure to adult female olfactory cues.

Several previous lines of research have suggested, indirectly, that mouse lifespan is particularly susceptible to endocrine or nutritional signals in the first few weeks of life, as tested by manipulations of litter size, growth hormone levels, or mutations with effects specifically on early-life growth rate. The pace of early development in mice can also be influenced by exposure of nursing and weanling mice to olfactory cues. In particular, odors of same-sex adult mice can in some circumstances delay maturation. We hypothesized that olfactory information might also have a sex-specific effect on lifespan, and we show here that the lifespan of female mice can be increased significantly by odors from adult females administered transiently, that is from 3 days until 60 days of age. Female lifespan was not modified by male odors, nor was male lifespan susceptible to odors from adults of either sex. Conditional deletion of the G protein Gαo in the olfactory system, which leads to impaired accessory olfactory system function and blunted reproductive priming responses to male odors in females, did not modify the effect of female odors on female lifespan. Our data provide support for the idea that very young mice are susceptible to influences that can have long-lasting effects on health maintenance in later life, and provide a potential example of lifespan extension by olfactory cues in mice.

Neuroendocrine Blockade of the Reproductive Axis in Female Athletes

This review aims at defining the neuroendocrine mechanisms underlying the sport-induced restrictions of the reproductive axis in female athletes. Episodic gonadotropin release was found to be compromised, presumably a result of impaired hypothalamic pulsatile GnRH release. Any deviation from optimal gonadotropin release may result in a suboptimal function of the ovaries, leading to disorders of the menstrual cycle and ovulation. A whole spectrum of menstrual dysfunctions ranging from ovulatory eumenorrhea to luteal phase defects and amenorrhea has been reported in sportive women. As essential neuroendocrine factors underlying these observations, activation of the adrenal axis and altered central nervous neurotransmitter activity have been identified to transfer metabolic, nutritional, and stress signals into the hypothalamic GnRH release. The degree by which the neuroendocrine axis governing reproduction is impaired critically depends on the intensity and duration of exercise and the state of training. Other decisive factors may be energy expenditure and availability, nutritional components, and the maturity of the hypothalamic-pituitary-ovarian (HPO) axis when sport activity was initiated. In conclusion, the gradual cessation of reproductive function observed in female athletes may be interpreted as an adaptive mechanism in response to physical and psychological endurance during sport. This sport-induced restriction of reproductive capacity may serve as protection (endogenous contraception) to preserve a woman’s health.

The Amino Acid Permease MoGap1 Regulates TOR Activity and Autophagy in Magnaporthe oryzae.

Rice is an important food crop all over the world. It can be infected by the rice blast fungus Magnaporthe oryzae, which results in a significant reduction in rice yield. The infection mechanism of M. oryzae has been an academic focus for a long time. It has been found that G protein, AMPK, cAMP-PKA, and MPS1-MAPK pathways play different roles in the infection process. Recently, the function of TOR signaling in regulating cell growth and autophagy by receiving nutritional signals generated by plant pathogenic fungi has been demonstrated, but its regulatory mechanism in response to the nutritional signals remains unclear. In this study, a yeast amino acid permease homologue MoGap1 was identified and a knockout mutant of MoGap1 was successfully obtained. Through a phenotypic analysis, a stress analysis, autophagy flux detection, and a TOR activity analysis, we found that the deletion of MoGap1 led to a sporulation reduction as well as increased sensitivity to cell wall stress and carbon source stress in M. oryzae. The ΔMogap1 mutant showed high sensitivity to the TOR inhibitor rapamycin. A Western blot analysis further confirmed that the TOR activity significantly decreased, which improved the level of autophagy. The results suggested that MoGap1, as an upstream regulator of TOR signaling, regulated autophagy and responded to adversities such as cell wall stress by regulating the TOR activity.

GLUT2 expression by glial fibrillary acidic protein-positive tanycytes is required for promoting feeding-response to fasting

Feeding behavior is a complex process that depends on the ability of the brain to integrate hormonal and nutritional signals, such as glucose. One glucosensing mechanism relies on the glucose transporter 2 (GLUT2) in the hypothalamus, especially in radial glia-like cells called tanycytes. Here, we analyzed whether a GLUT2-dependent glucosensing mechanism is required for the normal regulation of feeding behavior in GFAP-positive tanycytes. Genetic inactivation of Glut2 in GFAP-expressing tanycytes was performed using Cre/Lox technology. The efficiency of GFAP-tanycyte targeting was analyzed in the anteroposterior and dorsoventral axes by evaluating GFP fluorescence. Feeding behavior, hormonal levels, neuronal activity using c-Fos, and neuropeptide expression were also analyzed in the fasting-to-refeeding transition. In basal conditions, Glut2-inactivated mice had normal food intake and meal patterns. Implementation of a preceeding fasting period led to decreased total food intake and a delay in meal initiation during refeeding. Additionally, Glut2 inactivation increased the number of c-Fos-positive cells in the ventromedial nucleus in response to fasting and a deregulation of Pomc expression in the fasting-to-refeeding transition. Thus, a GLUT2-dependent glucose-sensing mechanism in GFAP-tanycytes is required to control food consumption and promote meal initiation after a fasting period.

Bacterial conversion of a host weapon into a nutritional signal

Bacteria engulfed by phagocytic cells must resist oxidation damage and adapt to cellular hypoxia, but the mechanisms involved in this process are not completely elucidated. Recent work by Kim etal. in the Journal of Biological Chemistry investigated how the intracellular pathogen Salmonella enterica activates gene expression required to counteract oxidative damage. The authors show that this bacterium utilizes host oxidative molecules to activate regulatory proteins that enhance the production of effector molecules, counteracting the host weapon NADPH oxidase and inducing a protective response.

Conserved roles for Hnf4 family transcription factors in zebrafish development and intestinal function.

Transcription factors play important roles in the development of the intestinal epithelium and its ability to respond to endocrine, nutritional, and microbial signals. Hepatocyte nuclear factor 4 family nuclear receptors are liganded transcription factors that are critical for the development and function of multiple digestive organs in vertebrates, including the intestinal epithelium. Zebrafish have 3 hepatocyte nuclear factor 4 homologs, of which, hnf4a was previously shown to mediate intestinal responses to microbiota in zebrafish larvae. To discern the functions of other hepatocyte nuclear factor 4 family members in zebrafish development and intestinal function, we created and characterized mutations in hnf4g and hnf4b. We addressed the possibility of genetic redundancy amongst these factors by creating double and triple mutants which showed different rates of survival, including apparent early lethality in hnf4a; hnf4b double mutants and triple mutants. RNA sequencing performed on digestive tracts from single and double mutant larvae revealed extensive changes in intestinal gene expression in hnf4a mutants that were amplified in hnf4a; hnf4g mutants, but limited in hnf4g mutants. Changes in hnf4a and hnf4a; hnf4g mutants were reminiscent of those seen in mice including decreased expression of genes involved in intestinal function and increased expression of cell proliferation genes, and were validated using transgenic reporters and EdU labeling in the intestinal epithelium. Gnotobiotics combined with RNA sequencing also showed hnf4g has subtler roles than hnf4a in host responses to microbiota. Overall, phenotypic changes in hnf4a single mutants were strongly enhanced in hnf4a; hnf4g double mutants, suggesting a conserved partial genetic redundancy between hnf4a and hnf4g in the vertebrate intestine.

DDIT3 regulates key enzymes in the methionine cycle and flux during embryonic development

One-carbon metabolism is a key metabolic network that integrates nutritional signals with embryonic development. However, the response of one-carbon metabolism to methionine status and the regulatory mechanisms are poorly understood. Herein, we found that methionine supplementation during pregnancy significantly increased fetal number and average fetal weight. In addition, methionine modulated one-carbon metabolism primarily through 2 metabolic enzymes, cystathionine β-synthase (CBS) and methionine adenosyltransferase 2A (MAT2A), which were significantly increased in fetal liver tissues and porcine trophoblast (pTr) cells in response to proper methionine supplementation. CBS and MAT2A overexpression enhanced the DNA synthesis in pTr cells. More importantly, we identified a transcription factor, DNA damage-inducible transcript 3 (DDIT3), that was the primary regulator of CBS and MAT2A, which bound directly to promoters and negatively regulated the expression of CBS and MAT2A. Taken together, our findings identified that DDIT3 targeting CBS and MAT2A was a novel regulatory pathway that mediated cellular one-carbon metabolism in response to methionine signal and provided promising targets to improve pregnancy health.

RNA interference knockdown of insulin receptor inhibits ovarian development in Chilo suppressalis.

The nutritional signaling pathway regulates an insect's size, development, and lifespan, as well as playing a vital role in reproduction. The insulin/insulin-like growth factor signaling (IIS) pathway plays a key role in the nutrition signaling pathway. As an integral component of the IIS pathway, insulin receptor (InR), a receptor tyrosine kinase, plays a role in the insulin pathway by controlling reproduction in many insect species. However, the precise molecular function of InR in non-model insect reproduction is poorly understood. In our study, Chilo suppressalis, a well-known rice pest, was used as a molecular system to determine the role of InR in insect reproduction. Sequencing the InR gene of C. suppressalis, comparing the amino acid sequence-specific structure, and constructing a phylogenetic tree revealed that this gene has four main domains: ligand binding L domain, Furin-like region, fibronectin type III domains, and Tyrosine kinase catalytic domain, which were all highly conserved in insects. By characterizing the spatiotemporal expression profile of InR in different developmental stages and tissues, we found that InR gene expression was highest on the 3-day old in female pupae, 6th instar larvae, and fat body on the 6-day old in female pupae. InR gene expression may promote the molting and pupation of larvae and play a role in reproduction in the fat body. Furthermore, the RNA interference knockdown of InR dramatically reduced yolk deposition and blocked oocyte maturation. After suppression of InR, the expression of several other genes fluctuated to varying degrees. In conclusion, InR is vital to reproduction and is expected to become a new target for pest management.

Analysis of the Stimulative Effect of Tryptophan on Hepatic Protein Synthesis in Rats.

Tryptophan is an essential amino acid important as a protein building block, but it also serves as substrate for the generation of several bioactive compounds with important physiological roles. Furthermore, tryptophan has been reported to have a unique role as a nutritional signaling molecule that regulates protein synthesis in mouse and rat liver. In the present study, the acute effects of tryptophan on protein synthesis were confirmed and compared with those of leucine in rats. Eighteen hours fasted rats were orally administered of tryptophan or leucine at a dose of 135 mg/100 g body weight by gavage and then sacrificed 1 h after administration. The effects of tryptophan and leucine on the rate of protein synthesis were evaluated by the surface sensing of translation (SUnSET) method. We also examined the ability of tryptophan to induce activation of the mTOR pathway by measuring phosphorylation of 4E-BP1 and S6K1. Oral administration of tryptophan led to a stimulation of the rate of protein synthesis concomitant with activation of mTOR pathway in the liver, but not in skeletal muscle. We also investigated the sensitivity of liver protein synthesis to tryptophan administration. The half-maximal effective doses (ED50) of tryptophan in stimulating 4E-BP1 and S6K1 phosphorylation were both about 60% of daily intake. The effect of tryptophan on hepatic protein synthesis was similar to that of leucine on muscle protein synthesis, and the sensitivity of liver protein synthesis to tryptophan administration appeared to be almost the same or slightly lower than that of muscle protein synthesis to leucine administration.

Nutrition-dependent juvenile hormone sensitivity promotes flight-muscle degeneration during the aphid dispersal-reproduction transition.

In insects, the loss of flight typically involves a dispersal-reproduction transition, but the underlying molecular mechanisms remain poorly understood. In the parthenogenetic pea aphid Acyrthosiphon pisum, winged females undergo flight-muscle degeneration after flight and feeding on new host plants. Similarly, topical application of a juvenile hormone (JH) mimic to starved aphids also induces flight-muscle degeneration. We found that feeding preferentially upregulated the expression of the JH receptor gene Met and a JH-inducible gene, Kr-h1, in the flight muscles, and, thus, enhanced tissue-specific JH sensitivity and signaling. RNAi-mediated knockdown of Kr-h1 prevented flight-muscle degeneration. Likewise, blocking nutritional signals by pharmacological inhibition of the target of rapamycin complex 1 (TORC1) impaired JH sensitivity of the flight muscles in feeding aphids and subsequently delayed muscle degeneration. RNA-sequencing analysis revealed that enhanced JH signaling inhibited the transcription of genes involved in the tricarboxylic acid cycle, likely resulting in reduction of the energy supply, mitochondrial dysfunction and muscle-fiber breakdown. This study shows that nutrient-dependent hormone sensitivity regulates developmental plasticity in a tissue-specific manner, emphasizing a relatively underappreciated mechanism of hormone sensitivity in modulating hormone signaling.

Nutritional and metabolic signalling through GPCRs.

Deregulated metabolism is a well-known feature of several challenging diseases, including diabetes, obesity and cancer. Besides their important role as intracellular bioenergetic molecules, dietary nutrients and metabolic intermediates are released in the extracellular environment. As such, they may achieve unconventional roles as hormone-like molecules by activating cell surface G-protein-coupled receptors (GPCRs) that regulate several pathophysiological processes. In this review, we provide an insight into the role of lactate, succinate, fatty acids, amino acids as well as ketogenesis-derived and β-oxidation-derived intermediates as extracellular signalling molecules. Moreover, the mechanisms by which their cognate metabolite-sensing GPCRs integrate nutritional and metabolic signals with specific intracellular pathways will be described. A better comprehension of these aspects is of fundamental importance to identify GPCRs as novel druggable targets.

Review: Influence of postabsorptive metabolism on essential amino acid partitioning in lactating dairy cows

In the lactating cow, essential amino acids (EAAs) absorbed from the gut are partitioned to mammary and extra-mammary tissues via blood plasma circulation. There is also entry of EAA into plasma from the breakdown of proteins in the cow’s body. A balance model across plasma was solved to integrate entry rates of branched-chain (BCAA) and non-branched-chain EAA (NBAA) with their corresponding rate constants for clearance by mammary glands and the remainder of the body, for selected glucose and fat infusion experiments. Endogenous EAA entry from whole-body proteolysis was reduced by glucose and unchanged or increased by fat, the efficiency of net plasma BCAA clearance by mammary and extra-mammary tissues was elevated by glucose but slightly reduced by fat, and the efficiency of extra-mammary NBAA clearance may have decreased during glucose infusion but it was not affected or slightly increased by fat. These differences between glucose and fat responses can be accounted for by insulin and glucagon. Insulin suppresses endogenous EAA entry through mechanistic target of rapamycin complex 1, integrated stress response, and glycogen synthase kinase 3 signaling networks in skeletal muscle. While these networks can also regulate protein synthesis rates in muscle and the extra-mammary body, they exhibit low sensitivities to insulin in lactating ruminants. However, in the mammary glands, via these same networks, insulin stimulates clearance of EAA from plasma, although the drive to maintain a set point for milk protein yield takes precedence over nutritional signals. The glucose-induced increase in mammary BCAA clearance without an effect on NBAA clearance is due to a pronounced decrease in plasma BCAA concentrations. Because NBAAs do not experience a similar decline in concentration, the BCAA effect must be due to their metabolic transformation as opposed to sequestration in proteins. In adipose, the products of BCAA catabolism are lipogenic precursors. We propose that faster lipogenesis in adipose tissue, stimulated by glucose infusion, also promotes the uptake of precursor BCAA from plasma, causing a drop in their circulating concentrations. In addition, insulin stimulates BCAA oxidation in muscle as an alternative fuel to fatty acids. A lower efficiency of extra-mammary NBAA clearance during glucose infusion may be the consequence of decreased hepatic expression of AA-catabolizing enzymes in response to low glucagon concentration. The proportion of EAA entry partitioned to the mammary glands is a culmination of regulatory shifts at all of the points discussed above according to a regulated or unfair competition between mammary and extra-mammary processes.

Molecular characterization of insulin receptor (IR) in oriental fruit moth, Grapholita molesta (Lepidoptera: Tortricidae), and elucidation of its regulatory roles in glucolipid homeostasis and metamorphosis through interaction with miR-982490.

As an intermediate molecule in the Insulin/Insulin-like growth factor signalling pathway (IIS), the insulin receptor (IR) plays vital roles linking nutritional signals to the downstream regulation of metabolic homeostasis, development, metamorphosis, reproduction and stress responses. In the present study, we describe the molecular characteristics of IR in the cosmopolitan fruit boring pest, Grapholita molesta, and its predicted posttranscription regulator miR-982490, and elucidate its regulatory roles in glucolipid homeostasis and metamorphosis. Phylogenetic and domain analyses indicate that lepidopteran IRs normally cluster within families, and that four main domains are conserved in GmIR and those of other Lepidoptera. Bio-informatic prediction, synchronic expression profile evaluation and dual luciferase reporter assays indicated negative regulation of GmIR by miR-982490. Injection of miR-982490 agomir into fifth instar larvae yielded effects similar to dsGmIR injection, resulting in enhanced levels of trehalose and triglyceride in haemolymph, and reduced pupation success and pupal weight, both of which could be rescued by co-injection of dsGmIR and miR-982490 antagomir. We infer that GmIR regulates glucolipid homeostasis and affects G. molesta metamorphosis via interactions with its posttranscriptional regulator miR-982490. This study expands our understanding of the regulatory network of IIS in insect nutritional homeostasis and development.

Nutrient sensing, signaling transduction, and autophagy in podocyte injury: implications for kidney disease.

Podocytes are terminally differentiated epithelial cells of the renal glomerular tuft and these highly specialized cells are essential for the integrity of the slit diaphragm. The biological function of podocytes is primarily based on a complex ramified structure that requires sufficient nutrients and a large supply of energy in support of their unique structure and function in the glomeruli. Of note, the dysregulation of nutrient signaling and energy metabolic pathways in podocytes has been associated with a range of kidney diseases i.e., diabetic nephropathy. Therefore, nutrient-related and energy metabolic signaling pathways are critical to maintaining podocyte homeostasis and the pathogenesis of podocyte injury. Recently, a growing body of evidence has indicated that nutrient starvation induces autophagy, which suggests crosstalk between nutritional signaling with the modulation of autophagy for podocytes to adapt to nutrient deprivation. In this review, the current knowledge and advancement in the understanding of nutrient sensing, signaling, and autophagy in the podocyte biology, injury, and pathogenesis of kidney diseases is summarized. Based on the existing findings, the implications and perspective to target these signaling pathways and autophagy in podocytes during the development of novel preventive and therapeutic strategies in patients with podocyte injury-associated kidney diseases are discussed.