A theoretical perspective on Waddington's genetic assimilation experiments.

Genetic assimilation is the process by which a phenotype that is initially induced by an environmental stimulus becomes stably inherited in the absence of the stimulus after a few generations of selection. While the concept has attracted much debate after being introduced by C. H. Waddington 70 y ago, there have been few experiments to quantitatively characterize the phenomenon. Here, we revisit and organize the results of Waddington's original experiments and follow-up studies that attempted to replicate his results. We then present a theoretical model to illustrate the process of genetic assimilation and highlight several aspects that we think require further quantitative studies, including the gradual increase of penetrance, the statistics of delay in assimilation, and the frequency of unviability during selection. Our model captures Waddington's picture of developmental paths in a canalized landscape using a stochastic dynamical system with alternative trajectories that can be controlled by either external signals or internal variables. It also reconciles two descriptions of the phenomenon-Waddington's, expressed in terms of an individual organism's developmental paths, and that of Bateman in terms of the population distribution crossing a hypothetical threshold. Our results provide theoretical insight into the concepts of canalization, phenotypic plasticity, and genetic assimilation.

Biodiversity and Constrained Information Dynamics in Ecosystems: A Framework for Living Systems.

The increase in ecosystem biodiversity can be perceived as one of the universal processes converting energy into information across a wide range of living systems. This study delves into the dynamics of living systems, highlighting the distinction between ex post adaptation, typically associated with natural selection, and its proactive counterpart, ex ante adaptability. Through coalescence experiments using synthetic ecosystems, we (i) quantified ecosystem stability, (ii) identified correlations between some biodiversity indexes and the stability, (iii) proposed a mechanism for increasing biodiversity through moderate inter-ecosystem interactions, and (iv) inferred that the information carrier of ecosystems is species composition, or merged genomic information. Additionally, it was suggested that (v) changes in ecosystems are constrained to a low-dimensional state space, with three distinct alteration trajectories-fluctuations, rapid environmental responses, and long-term changes-converging into this state space in common. These findings suggest that daily fluctuations may predict broader ecosystem changes. Our experimental insights, coupled with an exploration of living systems' information dynamics from an ecosystem perspective, enhance our predictive capabilities for natural ecosystem behavior, providing a universal framework for understanding a broad spectrum of living systems.

Homeorhesis: envisaging the logic of life trajectories in molecular research on trauma and its effects.

What sets someone on a life trajectory? This question is at the heart of studies of 21st-century neurosciences that build on scientific models developed over the last 150 years that attempt to link psychopathology risk and human development. Historically, this research has documented persistent effects of singular, negative life experiences on people's subsequent development. More recently, studies have documented neuromolecular effects of early life adversity on life trajectories, resulting in models that frame lives as disproportionately affected by early negative experiences. This view is dominant, despite little evidence of the stability of the presumably early-developed molecular traits and their potential effects on phenotypes. We argue that in the context of gaps in knowledge and the need for scientists to reason across molecular and phenotypic scales, as well as time spans that can extend beyond an individual's life, specific interpretative frameworks shape the ways in which individual scientific findings are assessed. In the process, scientific reasoning oscillates between understandings of cellular homeostasis and organisms' homeorhesis, or life trajectory. Biologist and historian François Jacob described this framework as the "attitude" that researchers bring to bear on their "objects" of study. Through an analysis of, first, historical and contemporary scientific literature and then ethnographic research with neuroscientists, we consider how early life trauma came to be associated with specific psychological and neurobiological effects grounded in understandings of life trajectories. We conclude with a consideration of the conceptual, ontological, and ethical implications of interpreting life trajectories as the result of the persistence of long-embodied biological traits, persistent life environments, or both.

Morphological homeostasis in the fossil record.

Morphological homeostasis limits the extent to which genetic and/or environmental variation is translated into phenotypic variation, providing generation-to-generation fitness advantage under a stabilizing selection regime. Depending on its lability, morphological homeostasis might also have a longer-term impact on evolution by restricting the variation-and thus the response to directional selection-of a trait. The fossil record offers an inviting opportunity to investigate whether and how morphological homeostasis constrained trait evolution in lineages or clades on long timescales (thousands to millions of years) that are not accessible to neontological studies. Fossils can also reveal insight into the nature of primitive developmental systems that might not be predictable from the study of modern organisms. The ability to study morphological homeostasis in fossils is strongly limited by taphonomic processes that can destroy, blur, or distort the original biological signal: genetic data are unavailable; phenotypic data can be modified by tectonic or compaction-related deformation; time-averaging limits temporal resolution; and environmental variation is hard to study and impossible to control. As a result of these processes, neither allelic sensitivity (and thus genetic canalization) nor macroenvironmental sensitivity (and thus environmental canalization) can be unambiguously assessed in the fossil record. However, homeorhesis-robustness against microenvironmental variation (developmental noise)-can be assessed in ancient developmental systems by measuring the level of fluctuating asymmetry (FA) in a nominally symmetric trait. This requires the analysis of multiple, minimally time-averaged samples of exquisite preservational quality. Studies of FA in fossils stand to make valuable contributions to our understanding of the deep-time significance of homeorhesis. Few empirical studies have been conducted to date, and future paleontological research focusing on how homeorhesis relates to evolutionary rate (including stasis), species survivorship, and purported macroevolutionary trends in evolvability would reap high reward.

Invited review: The influence of immune activation on transition cow health and performance-A critical evaluation of traditional dogmas.

The progression from gestation into lactation represents the transition period, and it is accompanied by marked physiological, metabolic, and inflammatory adjustments. The entire lactation and a cow's opportunity to have an additional lactation are heavily dependent on how successfully she adapts during the periparturient period. Additionally, a disproportionate amount of health care and culling occurs early following parturition. Thus, lactation maladaptation has been a heavily researched area of dairy science for more than 50 yr. It was traditionally thought that excessive adipose tissue mobilization in large part dictated transition period success. Further, the magnitude of hypocalcemia has also been assumed to partly control whether a cow effectively navigates the first few months of lactation. The canon became that adipose tissue released nonesterified fatty acids (NEFA) and the resulting hepatic-derived ketones coupled with hypocalcemia lead to immune suppression, which is responsible for transition disorders (e.g., mastitis, metritis, retained placenta, poor fertility). In other words, the dogma evolved that these metabolites and hypocalcemia were causal to transition cow problems and that large efforts should be enlisted to prevent increased NEFA, hyperketonemia, and subclinical hypocalcemia. However, despite intensive academic and industry focus, the periparturient period remains a large hurdle to animal welfare, farm profitability, and dairy sustainability. Thus, it stands to reason that there are alternative explanations to periparturient failures. Recently, it has become firmly established that immune activation and the ipso facto inflammatory response are a normal component of transition cow biology. The origin of immune activation likely stems from the mammary gland, tissue trauma during parturition, and the gastrointestinal tract. If inflammation becomes pathological, it reduces feed intake and causes hypocalcemia. Our tenet is that immune system utilization of glucose and its induction of hypophagia are responsible for the extensive increase in NEFA and ketones, and this explains why they (and the severity of hypocalcemia) are correlated with poor health, production, and reproduction outcomes. In this review, we argue that changes in circulating NEFA, ketones, and calcium are simply reflective of either (1) normal homeorhetic adjustments that healthy, high-producing cows use to prioritize milk synthesis or (2) the consequence of immune activation and its sequelae.

Transcriptome analyses of liver in newly-hatched chicks during the metabolic perturbation of fasting and re-feeding reveals THRSPA as the key lipogenic transcription factor.

BACKGROUND: The fasting-refeeding perturbation has been used extensively to reveal specific genes and metabolic pathways that control energy metabolism in the chicken. Most global transcriptional scans of the fasting-refeeding response in liver have focused on juvenile chickens that were 1, 2 or 4 weeks old. The present study was aimed at the immediate post-hatch period, in which newly-hatched chicks were subjected to fasting for 4, 24 or 48 h, then refed for 4, 24 or 48 h, and compared with a fully-fed control group at each age (D1-D4). RESULTS: Visual analysis of hepatic gene expression profiles using hierarchical and K-means clustering showed two distinct patterns, genes with higher expression during fasting and depressed expression upon refeeding and those with an opposing pattern of expression, which exhibit very low expression during fasting and more abundant expression with refeeding. Differentially-expressed genes (DEGs), identified from five prominent pair-wise contrasts of fed, fasted and refed conditions, were subjected to Ingenuity Pathway Analysis. This enabled mapping of analysis-ready (AR)-DEGs to canonical and metabolic pathways controlled by distinct gene interaction networks. The largest number of hepatic DEGs was identified by two contrasts: D2FED48h/D2FAST48h (968 genes) and D2FAST48h/D3REFED24h (1198 genes). The major genes acutely depressed by fasting and elevated upon refeeding included ANGTPL, ATPCL, DIO2, FASN, ME1, SCD, PPARG, SREBP2 and THRSPA-a primary lipogenic transcription factor. In contrast, major lipolytic genes were up-regulated by fasting or down-regulated after refeeding, including ALDOB, IL-15, LDHB, LPIN2, NFE2L2, NR3C1, NR0B1, PANK1, PPARA, SERTAD2 and UPP2. CONCLUSIONS: Transcriptional profiling of liver during fasting/re-feeding of newly-hatched chicks revealed several highly-expressed upstream regulators, which enable the metabolic switch from fasted (lipolytic/gluconeogenic) to fed or refed (lipogenic/thermogenic) states. This rapid homeorhetic shift of whole-body metabolism from a catabolic-fasting state to an anabolic-fed state appears precisely orchestrated by a small number of ligand-activated transcription factors that provide either a fasting-lipolytic state (PPARA, NR3C1, NFE2L2, SERTAD2, FOX01, NR0B1, RXR) or a fully-fed and refed lipogenic/thermogenic state (THRSPA, SREBF2, PPARG, PPARD, JUN, ATF3, CTNNB1). THRSPA has emerged as the key transcriptional regulator that drives lipogenesis and thermogenesis in hatchling chicks, as shown here in fed and re-fed states.

A 100-Year Review: Stress physiology including heat stress.

Stress is an external event or condition that places a strain on a biological system. The animal response to a stress involves the expenditure of energy to remove or reduce the impact of the stress. This increases maintenance requirements of the animal and results in loss of production. The biological response to stress is divided into acute and chronic phases, with the acute phase lasting hours to a few days and the chronic phase lasting several days to weeks. The acute response is driven by homeostatic regulators of the nervous and endocrine systems and the chronic phase by homeorhetic regulators of the endocrine system. Both responses involve alterations in energy balance and metabolism. Thermal environment affects all animals and therefore represents the largest single stressor in animal production. Other types of stressors include housing conditions, overcrowding, social rank, disease, and toxic compounds. "Acclimation" to a stress is a phenotypic response developed by the animal to an individual stressor within the environment. However, under natural conditions, it is rare for only one environmental variable to change over time. "Acclimatization" is the process by which an animal adapts to several stressors within its natural environment. Acclimation is a homeorhetic process that takes several weeks to occur and occurs via homeorhetic, not homeostatic, mechanisms. It is a phenotypic change that disappears when the stress is removed. When the stress is severe and not relieved by acclimatization or management changes, the animal is considered chronically stressed and is susceptible to increased incidence of disease and poor health. Milk yield and reproduction are extremely sensitive to stress because of the high energy and protein demands of lactation and the complexity of the reproductive process and multiple organs that are involved. Improvements in protection of animals against stress require improved education of producers to recognize stress and methods for estimating degree of stress on animals.

A 100-Year Review: Regulation of nutrient partitioning to support lactation.

We have seen remarkable advances in animal productivity in the last 75 years, with annual milk yield per cow increasing over 4-fold and no evidence of nearing a plateau. Because of these gains in productive efficiency, there have been dramatic reductions in resource inputs and the carbon footprint per unit of milk produced. The primary source for the historic gains relates to animal variation in nutrient partitioning. The regulation of nutrient use for productive functions has the overall goal of maintaining the cow's well-being regardless of the physiological or environmental challenges. From a conceptual standpoint, it involves both acute homeostatic controls operating on a minute-by-minute basis and chronic homeorhetic controls operating on a long-term basis to provide orchestrated adaptations that coordinate tissues and body processes. This endocrine regulation is mediated by changes in circulating anabolic and catabolic hormones, hormone membrane receptors and intracellular signaling pathways. The coordination of tissues and physiological systems includes a plethora of hormones, but insulin and somatotropin are 2 key regulators of nutrient trafficking. Herein, we review the advances in our understanding of both conceptual and actual regulation of nutrient partitioning in support of milk synthesis and identify examples of the challenges and future opportunities in dairy science.

Reducing milking frequency during nutrient restriction has no effect on the hepatic transcriptome of lactating dairy cattle.

The objective of this study was to investigate if a reduced milking frequency altered the effect of dietary energy restriction on the hepatic transcriptome of grazing dairy cows during early lactation. Multiparous Holstein-Friesian and Holstein-Friesian × Jersey cows (n = 120) were milked twice daily (2×) from calving until 34 ± 6 days in milk (mean ± SD). Cows were then allocated to one of four treatments in a 2 × 2 factorial arrangement. Treatments consisted of two milking frequencies [2× or once daily (1×)] and two feeding levels for 3 wk: adequately fed (AF) or underfed (UF, 60% of AF). Liver tissue was biopsied from 12 cows per treatment after 3 wk of treatment, and the hepatic transcriptome was profiled with an Agilent 4 × 44k bovine microarray. Over 2,900 genes were differentially expressed in response to the energy restriction; however, no effects resulted from changes to milking frequency. This may indicate that after 3 wk of 1× milking, any changes to the liver transcriptome that may have occurred earlier have returned to normal. After 3 wk of energy restriction, gene expression patterns indicate that glucose-sparing pathways were activated, and gluconeogenesis was increased in UF cows. Genes involved in hepatic stress were upregulated in response to the energy restriction indicative of the pressure energy restriction places on liver function. Other pathways upregulated included "cytoskeletal remodeling," indicating that a 3 wk energy restriction resulted in molecular changes to assist tissue remodeling. Overall, 1× milking does not modify the hepatic transcriptome changes that occur in response to an energy restriction.

Anti-inflammatory salicylate treatment alters the metabolic adaptations to lactation in dairy cattle.

Adapting to the lactating state requires metabolic adjustments in multiple tissues, especially in the dairy cow, which must meet glucose demands that can exceed 5 kg/day in the face of negligible gastrointestinal glucose absorption. These challenges are met through the process of homeorhesis, the alteration of metabolic setpoints to adapt to a shift in physiological state. To investigate the role of inflammation-associated pathways in these homeorhetic adaptations, we treated cows with the nonsteroidal anti-inflammatory drug sodium salicylate (SS) for the first 7 days of lactation. Administration of SS decreased liver TNF-α mRNA and marginally decreased plasma TNF-α concentration, but plasma eicosanoids and liver NF-κB activity were unaltered during treatment. Despite the mild impact on these inflammatory markers, SS clearly altered metabolic function. Plasma glucose concentration was decreased by SS, but this was not explained by a shift in hepatic gluconeogenic gene expression or by altered milk lactose secretion. Insulin concentrations decreased in SS-treated cows on day 7 compared with controls, which was consistent with the decline in plasma glucose concentration. The revised quantitative insulin sensitivity check index (RQUICKI) was then used to assess whether altered insulin sensitivity may have influenced glucose utilization rate with SS. The RQUICKI estimate of insulin sensitivity was significantly elevated by SS on day 7, coincident with the decline in plasma glucose concentration. Salicylate prevented postpartum insulin resistance, likely causing excessive glucose utilization in peripheral tissues and hypoglycemia. These results represent the first evidence that inflammation-associated pathways are involved in homeorhetic adaptations to lactation.

Ruminant Metabolic Diseases: Perturbed Homeorhesis.

The 6-week period encompassing parturition, termed the transition period, is recognized as the most fragile period in the life cycle of the ruminant animal. The period accounts for the greatest risk of health events that can adversely affect animal health, lactational performance, and future reproductive success. Critical endocrine and metabolic adaptations take place in allowing the animal to change nutrient priorities from supporting pregnancy to sustaining lactation. A reductionist perspective of underlying pathogenesis provided minimal metabolic disease prevalence improvement. Recent research has recognized metabolic regulatory complexity and role for activated inflammatory response underpinning dysregulation of homeorhesis during transition.

A consideration of physiological regulation from the perspective of Bayesian enactivism.

How the animal regulates its internal environment is a central question in physiology. In recent years, the account of biological functions known as Bayesian enactivism has been extended from neuroscience to address processes of physiological regulation. Enactivism understands sensory action cycles of perception and behaviour to entail expectations of the causes of sensations received from the environment. Enactivism is Bayesian in that the organism strives to update expectations to better match the sensations it experiences through actions. The review starts with a brief examination of the historical development of the concepts of homeostasis, homeorhesis and allostasis. To better align the historical concepts of physiological regulation with Bayesian enactivism it is suggested that homeorhesis and allostasis function as opposing effectors modulating, respectively, robustness and plasticity of phenotype to render homeostatic balance of the animal with its changing environment. In this formulation, the expectations of the environment embedded within the form and functions of the animal that develop under homeorhetic control during morphogenesis and morphostasis are updated by allostasis to better match the animal's phenotype with its contemporary environment. Just as morphogens shape development and persistence of anatomical form during morphogenesis and morphostasis, anticipatory behaviours can be understood to structure the animal's pattern of environmental engagement in a manner that shapes the development and persistence of homeostasis. Further empirical and theoretical analyses should help clarify whether homeorhesis and allostasis are aspects of a common underlying process or are opposing effectors mediating a Bayesian dialogue between expectation and experience.

Maternal Nicotinamide Riboside Enhances Postpartum Weight Loss, Juvenile Offspring Development, and Neurogenesis of Adult Offspring.

Conditions of metabolic stress dysregulate the NAD metabolome. By restoring NAD, nicotinamide riboside (NR) provides resistance to such conditions. We tested the hypotheses that postpartum might dysregulate maternal NAD and that increasing systemic NAD with NR might benefit mothers and offspring. In postpartum mothers, the liver NAD metabolome is depressed while blood increases circulation of NAD metabolites to enable a >20-fold increase in mammary NAD+ and NADP+. Lactation and NR synergize in stimulating prolactin synthesis and mammary biosynthetic programs. NR supplementation of new mothers increases lactation and nursing behaviors and stimulates maternal transmission of macronutrients, micronutrients, and BDNF into milk. Pups of NR-supplemented mothers are advantaged in glycemic control, size at weaning, and synaptic pruning. Adult offspring of mothers supplemented during nursing retain advantages in physical performance, anti-anxiety, spatial memory, delayed onset of behavioral immobility, and promotion of adult hippocampal neurogenesis. Thus, postgestational maternal micronutrition confers lasting advantages to offspring.

Hyper-restorative non-equilibrium state as a driving force of biological morphogenesis.

In 1935 Ervin Bauer formulated a basic principle of organization of living matter defined as the stable non-equilibrium state. The homeostatic stable non-equilibrium is realized internally by selecting the trajectories maintaining stable configurations from those disturbing it and supported by the dynamical structure of metabolism consisting of metabolic cycles, feedback loops and feedforward constraints. In the developing systems, according to Bauer, the principle of stable non-equilibrium is transformed into the principle of increasing external work which is grounded in the hyper-restorative non-equilibrium. The basis of this principle, as formulated by Lev Beloussov, is a hyper-restorative process during conformational relaxation of biomacromolecules which adds extra energy in the system and governs its complexification in which a new optimal coordinate pattern is searched. At the quantum level, this complexification is determined by the parametric refinement process in the field of possibilities. The complexification process takes place at the level of the cytoskeleton which represents a macroscopic enzymatic system and can generate differentiation waves that spread between cells. This may be associated with the function of cytoskeleton of transmitting signals and generating impulses. Different types of waves during morphogenesis correspond to different ranges of wavelengths of emission, from biophoton radiation to the hypersound waves in transmission of neural impulses. It is concluded that biological morphogenesis is based on the hyper-restorative non-equilibrium supported by the functional structure of the cytoskeleton.

Serotoninergic and Circadian Systems: Driving Mammary Gland Development and Function.

Since lactation is one of the most metabolically demanding states in adult female mammals, beautifully complex regulatory mechanisms are in place to time lactation to begin after birth and cease when the neonate is weaned. Lactation is regulated by numerous different homeorhetic factors, all of them tightly coordinated with the demands of milk production. Emerging evidence support that among these factors are the serotonergic and circadian clock systems. Here we review the serotoninergic and circadian clock systems and their roles in the regulation of mammary gland development and lactation physiology. We conclude by presenting our hypothesis that these two systems interact to accommodate the metabolic demands of lactation and thus adaptive changes in these systems occur to maintain mammary and systemic homeostasis through the reproductive cycles of female mammals.

Effects of heat stress on postabsorptive metabolism and energetics.

Environmental-induced hyperthermia compromises efficient animal production and jeopardizes animal welfare. Reduced productive output during heat stress was traditionally thought to result from decreased nutrient intake. Our observations challenge this dogma and indicate that heat-stressed animals employ novel homeorhetic strategies to direct metabolic and fuel selection priorities independent of nutrient intake or energy balance. Alterations in systemic physiology support a shift in carbohydrate metabolism, evident through changes such as basal and stimulated circulating insulin levels. Hepatocyte and myocyte metabolism also show clear differences in glucose production and use during heat stress. Perhaps most intriguing, given the energetic shortfall of the heat-stressed animal, is the apparent lack of fat mobilization from adipose tissue coupled with a reduced responsiveness to lipolytic stimuli. Thus, the heat stress response markedly alters postabsorptive carbohydrate, lipid, and protein metabolism independently of reduced feed intake through coordinated changes in fuel supply and utilization by multiple tissues.

Hypergravity disruption of homeorhetic adaptations to lactation in rat dams include changes in circadian clocks.

Altered gravity load induced by spaceflight (microgravity) and centrifugation (hypergravity) is associated with changes in circadian, metabolic, and reproductive systems. Exposure to 2-g hypergravity (HG) during pregnancy and lactation decreased rate of mammary metabolic activity and increased pup mortality. We hypothesize HG disrupted maternal homeorhetic responses to pregnancy and lactation are due to changes in maternal metabolism, hormone concentrations, and maternal behavior related to gravity induced alterations in circadian clocks. Effect of HG exposure on mammary, liver and adipose tissue metabolism, plasma hormones and maternal behavior were analyzed in rat dams from mid-pregnancy (Gestational day [G]11) through early lactation (Postnatal day [P]3); comparisons were made across five time-points: G20, G21, P0 (labor and delivery), P1 and P3. Blood, mammary, liver, and adipose tissue were collected for analyzing plasma hormones, glucose oxidation to CO(2) and incorporation into lipids, or gene expression. Maternal behavioral phenotyping was conducted using time-lapse videographic analyses. Dam and fetal-pup body mass were significantly reduced in HG in all age groups. HG did not affect labor and delivery; however, HG pups experienced a greater rate of mortality. PRL, corticosterone, and insulin levels and receptor genes were altered by HG. Mammary, liver and adipose tissue metabolism and expression of genes that regulate lipid metabolism were altered by HG exposure. Exposure to HG significantly changed expression of core clock genes in mammary and liver and circadian rhythms of maternal behavior. Gravity load alterations in dam's circadian system may have impacted homeorhetic adaptations needed for a successful lactation.

El papel de la insulina en la regulación de la síntesis de proteínas lácteas en bovinos / O papel da insulina na regulação da síntese das proteínas lácteas em bovinos / The role of insulin in the regulation of milky protein synthesis in cattle

No obstante la importancia nutricional e industrial de las proteínas lácteas, aún no están completamentecomprendidos los mecanismos que controlan su síntesis y concentración. Entre las distintas hormonasque regulan el metabolismo de la glándula mamaria, la insulina ha recibido mayor atención debidoa su estrecha relación con el metabolismo energético y proteico de los animales y debido al marcadoefecto que ha mostrado tener sobre la producción y concentración de proteínas lácteas. Existen al menostres mecanismos a través de los cuales esta hormona parece contribuir al incremento en la síntesis yconcentración de proteínas lácteas, los cuales son revisados en este documento: distribución de nutrienteshacia la glándula mamaria, regulación en la expresión de genes de caseínas e incremento en la tasa deiniciación de la síntesis de las proteínas a nivel postranscripcional.

In spite of the nutritional and industrial importance of milk proteins the mechanisms that controltheir synthesis and concentration still are not completely understood. Among the different hormonesthat participate in the mammary gland metabolism, insulin has received higher attention due to its closerelationship with the energetic and protein metabolism in dairy cows and to its marked effect on theproduction and concentration of milk proteins. There are at least three mechanisms by which this hormoneseems to contribute to increase in the synthesis and concentration of milk protein that are reviewed in this paper: nutrient distribution to mammary gland, regulation of gene expression of caseins and the rate ofinitiation of protein synthesis at post-transcriptional level.

Não obstante a importância nutricional e industrial das proteínas lácteas, ainda não estão completamentecompreendidos os mecanismos que controlam seu interesse e concentração. Entre os diferentes hormôniosque regulam o metabolismo da glândula mamaria, a insulina há recebido maior atenção devido a suaestreita relação com o metabolismo energético e protéico dos animais e devido ao mercado, efeito que temmostrado sobre a produção e concentração das proteínas lácteas. Existem pelo menos três marcadores atraves dos quais este hormônio parece contribuir ao incremento na síntese e concentração das proteínaslácteas, os quais são revisados: distribuição de nutrientes até a glândula mamária, regulação na expressãode genes de caseínas e incremento na taxa de iniciação da síntese das proteínas a nível pós transcripcional.