Maternal Nutrition and Hypothalamic Programming of Offspring Metabolic Health

Abstract

The hypothalamus plays a central role in regulating metabolism by integrating hormonal and nutrient-derived signals to maintain energy homeostasis across the life span. Maternal nutritional status during critical windows of development is a major environmental factor that can permanently alter this regulation. Both maternal overnutrition and undernutrition have been shown to disturb circulating leptin, insulin, and glucagon-like peptide-1 (GLP-1), and to disrupt the normal development of hypothalamic nuclei implicated in energy balance. Experimental and clinical studies indicate that these insults miswire proopiomelanocortin (POMC) and neuropeptide Y/ agouti-related peptide (NPY/AgRP) pathways, alter leptin and insulin receptor signaling, trigger neuroinflammation, glial and vascular changes, and are accompanied by enduring epigenetic alterations, including DNA methylation and chromatin remodelling at genes such as Pomc, Npy, Mc4r, Lepr and Insr. Together, these adaptations establish new set points for appetite, energy expenditure, and glucose regulation, thereby increasing the lifelong risk of obesity and type 2 diabetes in the offspring. In this narrative review, we synthesize evidence from animal models and human studies linking maternal nutrition to hypothalamic programming via leptin, insulin, and GLP-1. We also highlight major gaps, including limited data on GLP-1 in maternal undernutrition, the specific role of individual micronutrients, and the timing and reversibility of hypothalamic programming, to inform future mechanistic, translational, and preventive research.

Introduction

The global burden of obesity, type 2 diabetes (T2D), and metabolic syndrome has reached epidemic proportions in both adult and pediatric populations worldwide (1,2). Epidemiological data demonstrate a consistent rise in prevalence, with obesity predicted to reach 21% for women and 18% for men globally by 2025 (3). This alarming trend underscores the critical importance of identifying early-life risk factors that predispose individuals to metabolic dysfunction later in life, as chronic complications of childhood obesity often lead to adult metabolic syndrome (2). Obesity prevention critically requires a focus on the perinatal period (4).

A pivotal concept in understanding the long-term impact of early-life exposures is the ‘Developmental Origins of Health and Disease’ (DoHaD) hypothesis, which states that environmental factors during periconceptual, fetal, and early postnatal stages, particularly maternal nutrition, significantly program individual susceptibility to adult obesity and metabolic syndrome (1,5). These early-life adaptations, while potentially beneficial for immediate survival in suboptimal intrauterine conditions, can become maladaptive when offspring encounter abundant dietary environments later in life, thus contributing to adverse health outcomes. The DOHaD hypothesis is strongly supported by classic human epidemiological studies showing that maternal undernutrition during pregnancy is associated with increased later-life metabolic risk in offspring.

The timing of nutritional deprivation during gestation can critically influence specific metabolic impairments observed in offspring. Complementing human data, extensive animal models, including rodents and non-human primates, have been instrumental in elucidating developmental programming mechanisms (6–11). These studies consistently show that maternal undernutrition or overnutrition leads to long-term metabolic consequences in offspring, such as increased susceptibility to obesity, insulin resistance, type 2 diabetes, hypertension, and cardiovascular dysfunction (6,7,12–14). Notably, maternal HFD in rodent models often induces offspring phenotypes closely resembling human metabolic syndrome, and in larger animal models, both maternal under- and overnutrition result in similar long-term metabolic problems (13,15).

At the core of energy homeostasis is the hypothalamus, a critical brain region that integrates hormonal and nutrient signals from the periphery, including leptin, insulin, and glucagon-like peptide 1 (GLP-1), to regulate appetite, energy expenditure, and glucose balance (6,16–18). The developing hypothalamus is particularly vulnerable during gestational and early postnatal life, when alterations in the metabolic and hormonal environment can lead to abnormal hypothalamic development and function (16). Early-life programming from suboptimal nutrition during prenatal and postnatal life can have significant and lasting effects on hypothalamic pathways controlling energy balance (7,16,19). Such suboptimal perinatal exposures can induce persistent changes in hypothalamic neurocircuits, including altered neuropeptide gene expression, neuronal cell numbers, and impaired formation of axonal projections (7,17). For instance, maternal obesity has been shown to lead to hyperphagic and obese offspring with dysregulated hypothalamic gene expression and reduced central leptin sensitivity (16,20–22). Given that leptin and insulin are strongly neurotrophic, their altered availability during these sensitive periods of developmental plasticity can underpin lasting structural and functional consequences within the hypothalamus (22).

Despite substantial progress, several critical gaps remain. In particular, the precise mechanisms by which maternal nutritional states selectively reprogram hypothalamic hormone signaling pathways are not fully understood. Moreover, whether these hormonal alterations are causative drivers of long-term metabolic dysfunction or secondary consequences of broader neurodevelopmental changes remains unclear. In this narrative review, we critically examine how maternal nutritional status influences offspring metabolic risk through alterations in hypothalamic development, with particular focus on “hypothalamic programming,” defined here as persistent structural and functional alterations in hypothalamic circuits regulating energy balance that arise during critical developmental windows (19). We further emphasize the roles of key hormonal signaling pathways, including leptin, insulin, and GLP-1, which link maternal nutrition to hypothalamic development, and later metabolic disease. Leptin and insulin act as long-term indicators of body fat and nutrient status, directly regulating neuropeptide Y (NPY)/ agouti-related peptide (AgRP), proopiomelanocortin (POMC)/ cocaine- and amphetamine-regulated transcript (CART) neurons in the arcuate nucleus (ARH) to adjust food intake and energy expenditure. GLP-1 is released from the gut and from the brainstem after a meal, and its receptor is expressed in several hypothalamic nuclei where it promotes satiety and supports glucose control (21–24). Experimental models of both maternal overnutrition and maternal undernutrition frequently report changes in these three hormone systems in parallel with altered hypothalamic wiring, and in human medicine, they are closely tied to obesity and type 2 diabetes. Given that terms describing maternal nutritional exposures are often used interchangeably across studies, we summarize and standardize these definitions in Table 1 for clarity.

Table 1.

Key definitions of maternal nutritional exposures

Category	Term	Definition	Relevant outcomes
Overnutrition	Maternal overnutrition	A broad state of excess caloric or macronutrient intake, which can be mild or chronic	Increased offspring adiposity and altered brain appetite regulators
	Maternal obesity	The physiological state of high adiposity or BMI (typically kg/m2 in humans) before and during pregnancy	Hyperleptinemia and insulin resistance in offspring, independent of diet composition.
Metabolic state	Gestational hyperglycemia	Elevated maternal blood glucose levels during pregnancy, often as a component of the metabolic profile in HFD or obese models	Direct association with offspring adiposity and increased birth weight.
Dietary models	High-fat diet	A refined, purified diet typically containing 25–50% kcal from fat (mostly saturated)	Increased risk of type 2 diabetes and obesity in male offspring
	Western diet	A diet high in calories, fats, and refined sugars. Often modeled via a “cafeteria diet” using processed human foods.	Stronger promotion of obesity due to high palatability and caloric load.
Undernutrition	Caloric restriction	A reduction in total energy intake is often used to model famine or food scarcity.	Low birth weight followed by accelerated postnatal growth and metabolic disease.
	Protein restriction	Specific reduction in protein intake, affecting placental amino acid transport and fetal glucocorticoid exposure.	Impaired organ-specific development and long-term metabolic dysregulation
	Micronutrient deficiency	Lack of essential vitamins/minerals (e.g., iron, zinc, folate, choline, Vitamin B12) regardless of total caloric intake	Increased risk of anemia, placental dysfunction, and neonatal morbidity

In this review, we conducted a targeted literature search in PubMed and Google Scholar, peer-reviewed articles published between January 2000 and April 2025, with the final search performed in August 2025, using combinations of terms such as “maternal overnutrition,” “maternal high-fat diet,” “maternal undernutrition,” “offspring hypothalamus,” “developmental programming,” “leptin,” “insulin,” and “GLP-1.” Titles and abstracts were initially screened for relevance, followed by full-text evaluation of selected articles. Studies were included if they investigated the effects of maternal nutritional exposures (e.g., high-fat diet, Western diet, maternal obesity, caloric restriction, protein restriction, or micronutrient deficiency) and reported hypothalamic developmental, neuroendocrine signaling, or metabolic outcomes in offspring. We prioritized mechanistic animal studies and included human observational or clinical studies that provided evidence related to fetal or neonatal hormonal exposure, hypothalamic function, or metabolic phenotypes in offspring, while excluding non-peer-reviewed sources, conference abstracts, editorials, and commentaries. Although seminal epidemiological and experimental studies published before 2000 established the developmental origins of health and disease (DoHaD) framework and its relevance to maternal nutrition, the present review focuses primarily on post-2000 literature to emphasize more recent mechanistic and translational advances in hypothalamic development, hormonal signaling, and offspring metabolic programming.

1. Hypothalamic Regulation of Energy Balance

The hypothalamus consists of several distinct nuclei with specialized roles in regulating energy homeostasis. Among these, ARH is central to processing metabolic and hormonal signals from the periphery. It contains critical neuronal populations responsible for appetite regulation and projects to various other hypothalamic areas (16,17,25). Notably, the paraventricular nucleus (PVN) integrates input from the ARH and influences both food intake and energy expenditure. It also plays a role in modulating stress responses via the hypothalamic-pituitary-adrenal (HPA) axis (18,26,27). The ventromedial hypothalamus (VMH) functions in glucose sensing and satiety, and damage to this area has long been associated with overeating and obesity (28,29). The dorsomedial hypothalamus (DMH) is involved in energy balance regulation and also receives signals from the ARH (16,30). Meanwhile, the lateral hypothalamic area (LHA), often referred to as a feeding center, promotes food-seeking behavior and is essential for maintaining normal appetite; lesions here typically cause reduced food intake (31).

Energy balance is maintained through opposing actions of orexigenic and anorexigenic neurons within interconnected hypothalamic nuclei. NPY/AgRP neurons in the ARH stimulate food intake and suppress energy expenditure, particularly during energy deficit states (23,32–34). Their activity is counteracted by anorexigenic populations such as POMC and CART neurons, which inhibit feeding and promote energy use. Their expression is upregulated during periods of high energy intake and reduced during fasting (8,30,34). The POMC-derived peptide alpha-melanocyte-stimulating hormone (α-MSH) activates MC4R to inhibit food intake (18,23,35). The activity of these neuronal populations is critically modulated by peripheral hormones: leptin and insulin activate POMC neurons and inhibit NPY/AgRP neurons to reduce food intake and increase energy expenditure (16,20,23,33,34).

In the following sections, we describe how maternal overnutrition and undernutrition disrupt these hormonal and neural systems to program life-long susceptibility to metabolic disease.

2. Maternal Overnutrition and the Hypothalamus

Maternal nutrient excess, or maternal overnutrition, refers to a state in which maternal energy intake and adiposity are chronically elevated before and during pregnancy and lactation, typically in the context of pre-pregnancy obesity, excessive gestational weight gain, and Western-style diets rich in saturated fat, added sugars, and ultra-processed, energy-dense foods (24,30,36–38). The excessive nutrient intake during pregnancy leads to maternal insulin resistance, hyperglycemia, dyslipidemia, and low-grade inflammation, which changes the metabolic and hormonal environment of offspring during pregnancy and early postnatal period (20,36,39,40). Research using animal models has established that maternal overnutrition alters both hypothalamic structure and function in offspring.(41–43).

Rodents fed HFD during gestation and lactation produce offspring that become obese and exhibit increased food intake along with abnormal hypothalamic gene expression (44,45). For example, Page et al. (46) showed that dams fed a diet providing 45% of energy from saturated fat during the periconceptional period, pregnancy and lactation produced 120-day-old offspring with increased adiposity, altered fuel metabolism and changes in hypothalamic expression of Lepr, Pomc, Npy and reduced Npy1r. Similarly, Chen et al. (47)reported that maternal and postnatal overnutrition increased adiposity and insulin resistance in adult offspring and was accompanied by increased hypothalamic Npy/Y1r and reduced Pomc/Mc4r, changes consistent with reduced melanocortin tone (16). These metabolic disturbances are associated with disrupted development and function of POMC and NPY/AgRP pathways, including altered projections from ARH to the PVN in both mice and rats (48–50).Experimental evidence indicates that maternal consumption of a fat-rich diet during the lactation period alone can program metabolic dysfunction in offspring. Specifically, this exposure alters the development of ARH projections from POMC and AgRP neurons, contributing to increased risk of obesity and glucose intolerance in later life (48). In murine models, dams consuming energy-dense high-fat or high-fat/high-sucrose diets typically providing approximately 40–60% of total energy from fat compared with approximately 10% in standard chow produce adult offspring with excessive fat accumulation, reduced glucose clearance, and impaired insulin sensitivity(21,46,51,52).

Maternal overnutrition has been shown to induce a proinflammatory state within the developing hypothalamus. This inflammation, which involves the interaction between neurons and glial cells, can result in impaired neurodevelopment. Studies have demonstrated a decline in specific proliferative markers in neural progenitor populations. For example, Dearden et al.(19), identified a significant decrease in the expression of proliferative gene markers Bub1b, Ki67, and Pcna in the fetal hypothalamic tissue of offspring from obese pregnancies. Moreover, these studies also reported a reduction in neurosphere formation, meaning that hypothalamic neural progenitor cells from offspring exposed to maternal obesity produced fewer and smaller neurospheres when cultured in vitro (19). Furthermore, in an earlier study, Dearden et al.(19) reported that markers of neurogenesis and synaptic plasticity were also diminished in the hypothalamus of the offspring from obese mothers, indicating abnormal neuronal differentiation (18). This includes a significant reduction in the hypothalamic expression of crucial neurotrophic factors like brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB) (18), which are vital for neuronal differentiation and maturation. A critical outcome of early overnutrition is disruption of hypothalamic endocrine signaling via increased blood–brain barrier (BBB) permeability in the ARH, characterized by more fenestrated capillaries, loss of tanycytic processes and altered tight junction proteins such as claudin-5, occludin and ZO-1. This compromised barrier likely exposes developing hypothalamic circuits to abnormal leptin, insulin, and ghrelin levels and contributes to early hormone resistance (25).

Furthermore, exposure to Western-type diets during pregnancy leads to abnormal glucose metabolism in the fetal brain. Structural changes in hypothalamic connectivity, particularly in the LHA, may also sensitize offspring to obesity when challenged with energy-rich diets later in life (31). Clinical observations indicate that maternal or gestational diabetes mellitus (GDM) induces central insulin resistance and alters fetal brain activity (53) In a small fetal magnetoencephalography (fMEG) study, lower maternal insulin sensitivity was associated with delayed fetal brain responses to an oral glucose challenge, providing early evidence that maternal metabolism directly influences fetal brain function and may program central insulin resistance in utero (53). More recently, Magnetic Resonance Imaging (MRI) data from the BrainChild Study showed that children aged 7–11 years with in utero GDM exposure, particularly before 26 weeks of gestation, exhibit mediobasal hypothalamic gliosis(54). A related study reported similar MBH gliosis in children aged 9–11 years exposed to maternal diabetes or hypertension, supporting the concept of early hypothalamic dysfunction following adverse intrauterine metabolic environments (55). Together, these findings indicate that hypothalamic dysfunction after maternal overnutrition is well established in animal models, where neural circuitry, receptor signaling, and cellular changes can be directly measured. In humans, support is currently indirect and is based mainly on fetal hormone exposure, neuroimaging markers such as mediobasal hypothalamic gliosis, and later metabolic phenotypes, whereas direct evidence of specific hypothalamic circuit remodeling remains limited.

2.1. Impact of Maternal Overnutrition on Hypothalamic Hormonal Signaling

Maternal overnutrition profoundly disrupts hypothalamic hormonal signaling in offspring, particularly involving leptin, insulin, and GLP-1 resulting in dysregulation that is critical for metabolic control.

2.1.1. Leptin

Leptin, an adipocyte-derived hormone, serves as an essential regulator of energy balance. It functions centrally in the hypothalamus to suppress food consumption and enhance energy expenditure, while peripherally it aids in diminishing ectopic fat accumulation and sustaining glucose homeostasis (34,56,57). The long form of the leptin receptor (LepRb), highly expressed in the ARH, enables leptin to activate both NPY/AgRP and POMC/CART neurons, thereby restraining appetite (58). The LepRb signaling recruits Janus kinase-2 (JAK-2) and downstream STAT3, ERK, and Akt pathways (56,59), and loss of functional LepRb disrupts these cascades and leads to abnormal POMC and AgRP axonal connections in mice and rats (56).

Maternal overnutrition functions as a primary factor that leads to the development of leptin resistance in offspring, causing their bodies to lose sensitivity to leptin even when leptin levels remain high. The hypothalamus of offspring from obese mothers often develops insulin and leptin resistance as early in utero (20). Studies in pups born to obese dams showed reduced LepRb mRNA expression and blunted leptin-induced STAT3 activation in the hypothalamus, indicating impaired downstream LepRb signaling (60). The reduced leptin activity causes less suppression of food intake, thereby causing increased hunger and hyperphagia. Mechanistically, inflammatory signaling blunts leptin action by interfering with its intracellular pathways. Suppressor of cytokine signaling 3 (SOCS3) inhibits LepRb–Janus kinase 2 (JAK2) signaling, and IκB kinase-α (IKKα), c-Jun N-terminal kinase (JNK) and protein kinase C-θ (PKCθ) promote inhibitory serine phosphorylation of downstream intermediates (61–63).

Hyperleptinemia resulting from maternal obesity, especially in the presence of high sugar intake, increases hypothalamic NPY and activates peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein-1 (SREBP-1), and lipin-1 in visceral adipose tissue, which promotes lipid accumulation and reinforces leptin resistance (64,65).

The neonatal leptin surge is a crucial physiological event for the proper formation and maturation of hypothalamic neural circuits that govern appetite and energy balance (14,23,66). During this critical developmental window, leptin acts as a neurotrophic factor, directing the development of key feeding pathways, particularly ARH projections to the PVN (23,30,67). Proper hypothalamic development and metabolic homeostasis depend on maintaining a specific leptin threshold during early life (22,30). Deviations from this range, whether excessive or deficient, can lead to adverse long-term metabolic outcomes, consistent with a U-shaped relationship between neonatal leptin levels and adult metabolic health (44).

Maternal overnutrition can disrupt the neonatal leptin surge in two distinct ways. In many HFD models, offspring display an exaggerated or prolonged surge, resulting in neonatal hyperleptinemia often coupled with hyperinsulinemia (22). This pattern can persist into adulthood and contribute to the programming of obesity and leptin resistance (20,22). Such excessive leptin exposure during critical developmental windows can induce central leptin resistance and contribute to long-term dysregulation of hypothalamic energy-balance circuits, increasing susceptibility to hyperphagia, overeating, and adiposity in later life (6,8,16,20,22). Elevated leptin mRNA levels in neonatal adipose tissue indicate that this prolonged rise in circulating leptin is largely driven by endogenous leptin production rather than maternal transfer (20). Conversely, some maternal overnutrition models report reduced circulating leptin and insulin concentrations during the neonatal period, a condition referred to as neonatal hypoleptinemia and hypoinsulinemia (22,40). This early hormonal deficiency, also known as a blunted or drastically reduced postnatal leptin surge (66), similarly impairs hypothalamic development, leading to long-term metabolic dysregulation, including combined central insulin and leptin resistance in adulthood (22). In both animal models and clinical observations, newborn humans with either high or low leptin levels at birth have been shown to have a higher risk of developing obesity and T2D compared with those with normal leptin levels (22,44) suggesting a critical optimal range for neonatal leptin.

2.1.2. Insulin

Insulin, produced by pancreatic β-cells, plays a pivotal role in metabolic homeostasis, including central regulation of energy balance within the hypothalamus. In this brain region, insulin signaling through the IR-IRS-PI3K-Akt pathway modulates activity of key neuronal populations, such as anorexigenic POMC neurons and inhibits orexigenic AgRP/NPY neurons, thereby reducing food intake and influencing energy expenditure (29,68,69). This intricate central insulin signaling is crucial for maintaining normal energy and glucose homeostasis (29). Maternal high-fat feeding during lactation impairs hypothalamic neurocircuit formation in offspring. In mouse models, loss of insulin signaling in POMC neurons can prevent some of these alterations, such as impaired glucose-stimulated insulin secretion (17).

Maternal overnutrition, encompassing high-fat or obesogenic diets and gestational hyperglycemia, significantly alters insulin secretion and signaling in offspring. These conditions often manifest as fetal or neonatal hyperinsulinemia, a state observed in infants of diabetic mothers and in rodent neonates, which can persist into adulthood (68). In the hypothalamus, maternal overnutrition induces insulin resistance characterized by reduced phosphorylation and altered expression of insulin receptor, insulin receptor substrate (IRS) proteins, and Akt (20,68,69). Maternal obesity also causes fetal hypothalamic insulin resistance, with disrupted development of feeding pathways, reduced proliferation of neural precursor cells, and altered Notch signaling pathway (19). These changes contribute to an imbalanced ratio of anorexigenic and orexigenic signals in ARH and defective feeding regulation in adulthood (19). Beyond central hypothalamic effects, maternal HFD can also alter peripheral metabolic pathways in offspring. For example, maternal HFD increases offspring hepatic gluconeogenesis and glycolysis while reducing glycogen synthesis via AMPK, Akt, and IRS1 signaling, while upregulating SREBP1c and downregulating PPAR-α, thereby contributing to hepatic lipid accumulation and systemic insulin resistance (70). Animal models have been critical in defining these effects. For instance, rat models exposed to a HFD prior to and throughout pregnancy and lactation demonstrate offspring hyperinsulinemia and insulin resistance, alongside altered pancreatic β-cell function characterized by reduced β-cell number and volume (38,39). Similarly, maternal HFD during gestation and lactation, with a 60% lipid-rich diet, leads to increased weight gain and decreased glucose tolerance, in rat offspring, with gender-specific differences where female offspring exhibit attenuated effects with age while male offspring’s weight gain worsens (51). Maternal high-sugar diets during lactation in Wistar rats also induce hypothalamic insulin resistance, indicated by reduced IRS-β, PI3K, and Akt levels in adult offspring, contributing to hyperphagia and obesity (20). Mouse models fed an obesogenic diet during pregnancy and gestation show adult offspring with increased fat mass, decreased glucose tolerance, and insulin sensitivity, often linked to altered hypothalamic energy metabolism (52). Specifically, maternal HFD feeding, even pregestationally, results in increased body weight, elevated fasting blood glucose, and a significant increase in homeostatic model assessment indices of insulin resistance in offspring (17).

Human and clinical data consistently demonstrate a strong link between maternal obesity and hyperglycemia with adverse metabolic outcomes in offspring. Maternal obesity and diabetes complicate a significant percentage of pregnancies, predisposing offspring to metabolic disorders like obesity and T2DM later in life, often independently of genetic background (17). Offspring of obese mothers are at an increased risk for obesity, insulin resistance, and metabolic syndrome (71). During gestation, maternal insulin resistance leads to increased lipolysis, resulting in greater fetal exposure to free fatty acids, which can contribute to fetal obesity and insulin resistance (4) The phenomenon of fetal hyperinsulinemia, where the fetus produces excess insulin in response to maternal hyperglycemia, has long been recognized as an anabolic factor promoting fetal overgrowth, particularly in infants of diabetic mothers (4,28). This concept is central to the Pedersen hypothesis, which states that increased fetal glucose supply due to maternal diabetes stimulates fetal insulin secretion, resulting in macrosomia and an increased risk of obesity and T2DM in adulthood (28). Studies such as the Hyperglycemia and Adverse Pregnancy Outcomes study have reported a strong association between umbilical cord C-peptide levels and fetal adiposity, even in cases of maternal glucose concentrations are below the diagnostic threshold for overt diabetes (4). Children born to mothers with poorly controlled glycemia have a higher risk for metabolic syndrome, obesity, and T2DM in later life (53). Furthermore, human studies indicate that offspring of obese mothers develop hallmarks of insulin resistance in utero, highlighting that changes in the hypothalamic insulin signaling pathway can occur before birth, a direct consequence of the obese intrauterine environment (19). The fetal brain’s insulin resistance may represent a metabolic imprinting with significant consequences for later life, affecting brain activity and potentially leading to central insulin resistance (53). Thus, disrupted hypothalamic insulin signaling is mechanistically established in animal models, whereas in humans the evidence is suggestive but largely inferential, relying on maternal glycemia, cord or fetal metabolic markers, and functional or imaging-based readouts rather than direct measurement of hypothalamic insulin signaling pathways.

2.1.3. GLP-1

GLP-1 is an incretin hormone synthesized mainly by intestinal L-cells after meals and also derived from preproglucagon in pancreatic α-cells and selected brainstem neurons (23,72–74). Its receptor (GLP-1R) is expressed in the gut, pancreas, vagal afferents, brainstem, hippocampus and hypothalamic nuclei such as the ARH and PVN (28,73,75). Through these targets, GLP-1 slows gastric emptying, enhances glucose dependent insulin secretion, suppresses glucagon and reduces food intake. Within the hypothalamus, GLP-1 signaling decreases feeding and can lower neuropeptide Y expression, supporting an anorexigenic role in energy balance regulation (76). Importantly, although GLP-1 is well recognized for its metabolic actions in adults, emerging evidence suggests that GLP-1 signaling may also contribute to developmental programming through effects on maternal metabolic adaptation, placental function, and maturation of central feeding circuits. However, direct evidence for this role remains much stronger in animal models than in humans (77,78).

Maternal overnutrition, including high-fat and high-sugar diets, obesity, and gestational hyperglycaemia, can modify this system in both mother and offspring. In normal pregnancy, circulating maternal GLP-1 levels gradually decline while pancreatic islet GLP-1 content increases, which appears to support maternal metabolic adaptation and fetal growth (73,74). This decline may represent a physiological adaptation of pregnancy, as excessive GLP-1R activation during late gestation has been linked to fetal growth restriction in animal models (79). In addition, because active GLP-1 is rapidly degraded by DPP-4, and ex vivo placental perfusion studies suggest minimal transfer of exenatide across the human placenta, direct fetal exposure to maternal circulating GLP-1 or GLP-1 analogues is likely limited(79,80). Therefore, maternal GLP-1 may influence offspring development predominantly through indirect mechanisms, including altered metabolism and placental signaling, rather than robust transplacental passage (79). Obesity and overweight are associated with blunted GLP-1 responses to oral glucose, indicating a reduced incretin effect (76). In rodent models, offspring of obese dams show lower gut-derived plasma GLP-1 concentrations and males exposed to maternal HFD from preconception through lactation exhibit reduced serum GLP-1 and disturbed energy homeostasis (76,81). Maternal diet does not consistently change hypothalamic Glp1r expression at the mRNA or protein level, suggesting that altered GLP-1 secretion or post-receptor signaling, rather than receptor abundance, contributes to GLP-1 dysfunction. High-fat feeding can also blunt central responsiveness to GLP-1, consistent with a form of GLP-1 resistance in GLP-1 sensitive circuits (76,81). At the developmental level, evidence from animal studies further suggests that GLP-1R signaling is dynamically regulated during early life. In mice, hypothalamic GLP-1R expression shows age and region-specific patterns during the postnatal period, particularly in feeding-related nuclei, supporting the existence of a sensitive developmental window during which altered GLP1 signaling could influence maturation of hypothalamic circuits (78). Consistent with this possibility, neonatal GLP-1R activation has been shown to durably remodel hypothalamic architecture and limit later adiposity, indicating that GLP-1-sensitive pathways can shape long-term energy balance when perturbed during development (77).

Pharmacological activation of GLP-1R during pregnancy further illustrates the sensitivity of placental and fetal development to GLP-1 dynamics. In C57BL/6 mice, late gestation semaglutide treatment reduces fetal body weight and decreases placental labyrinth area and capillary density, indicating impaired fetoplacental vascular development when GLP-1 activity is excessive (74). In Sprague Dawley rats, maternal obesity induced by a cafeteria-style HFD produces heavier, glucose-intolerant offspring by postnatal day 20, and exendin 4 treatment lowers offspring body weight across maternal and postnatal diet groups, suggesting partial reversal of programmed metabolic dysfunction (40,72). Recombinant GLP-1 administration in pregnant A/J mice reduces fetal size and is associated with neonatal complications, highlighting the vulnerability of fetal growth and brain development to altered GLP-1 exposure (82,83). These pharmacological studies should, however, be interpreted cautiously. They are best viewed as natural experiments that reveal the sensitivity of fetal and placental development to exaggerated GLP-1R stimulation, rather than direct evidence of the normal physiological role of endogenous maternal GLP-1 in hypothalamic programming (79,84). Human data remain limited. Case series of inadvertent GLP-1R agonist exposure in early pregnancy have not shown a clear increase in major congenital malformations, and observational studies after bariatric surgery suggest improved maternal metabolism but a higher risk of small for gestational age offspring (73,82). Experimental evidence from a mouse sleeve-gastrectomy model further supports this concern, as elevated maternal GLP-1 after surgery was linked to small-for-gestational-age birth, GLP-1R antagonism during pregnancy normalized birth weight and improved later metabolic outcomes in offspring (84). Overall, maternal overnutrition and its treatment can substantially alter GLP-1 secretion, signaling and tissue responsiveness, with important implications for placental function, hypothalamic programming and long-term metabolic risk in the offspring (23,73,74,81). Future studies should therefore distinguish the effects of endogenous maternal GLP-1 from those of pharmacologic GLP-1R agonist exposure and directly test whether maternal GLP-1 alters offspring hypothalamic GLP-1R signaling, neuronal connectivity, or glial maturation during sensitive developmental windows (77,78).

2.2. Epigenetic alterations associated with maternal overnutrition

Beyond hormonal signaling abnormalities, maternal overnutrition also induces stable epigenetic changes in hypothalamic genes that regulate energy balance. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, represent critical regulatory layers that modulate gene expression without altering the underlying DNA sequence. These mechanisms are especially important for the long-term programming of hypothalamic circuits that regulate appetite, energy expenditure, and glucose homeostasis (13,24,85). When such marks are perturbed during sensitive developmental windows, they can permanently shift the set-point of neuroendocrine systems and predispose individuals to metabolic disease.

Maternal overnutrition, typically modeled by high-fat, high-sugar, or obesogenic diets, induces stable epigenetic changes in key hypothalamic genes involved in energy balance. In Sprague-Dawley rats, maternal consumption of a diet providing 60% energy from pre-mating through lactation produces offspring with increased adiposity and hyperleptinemia by postnatal day 21. In the same model, persistent promoter hypermethylation of the Pomc gene in the ARH is maintained into adulthood, preventing normal leptin-stimulated Pomc expression and thereby weakening anorexigenic signaling (1,21). By contrast, in a mouse model in which dams receive a high-fat, high-sucrose diet from pregnancy through 32 weeks of age, offspring display impaired glucose tolerance and elevated leptin levels alongside hypomethylation of the hypothalamic Pomc promoter and increased Pomc expression, suggesting model- and context-dependent effects of overnutrition on Pomc methylation and melanocortin pathway activity (85). Other studies have shown that maternal high-fat feeding during pregnancy increases DNA methylation in the Insr promoter in the offspring hypothalamus, leading to reduced Insr expression and decreased central insulin sensitivity, often with more pronounced effects in male offspring.

Rodent models of maternal obesity report reduced expression of anorexigenic Pomc and increased Npy in the ARH in early life, together with disrupted hypothalamic development and defective feeding regulation in adulthood. These transcriptional shifts are thought to reflect epigenetic regulation of neuropeptide genes and altered differentiation of hypothalamic neural progenitors (19,22). Maternal overnutrition during lactation further modifies methylation patterns at hypothalamic Insr and Pomc loci, contributing to central insulin and leptin insensitivity in offspring. Human evidence, associative rather than causal, supports a role for epigenetic programming. Placental and cord-blood samples from obese or diabetic pregnancies show altered DNA methylation at metabolic genes, consistent with stable programming of offspring energy balance and insulin sensitivity (37). However, most mechanistic epigenetic evidence remains derived from rodent models, whereas human data are limited and largely indirect. At present, the strongest evidence concerns DNA methylation changes at loci such as Pomc and Insr. Other epigenetic layers, including histone modifications, chromatin accessibility, and non-coding RNAs, remain comparatively understudied in the context of maternal overnutrition and offspring hypothalamic programming. Accordingly, cell-type-specific analyses within individual hypothalamic nuclei and well-designed longitudinal human studies will be needed to determine which epigenetic alterations are robust, translationally relevant, and causally linked to later metabolic dysfunction.

Collectively, these data indicate that maternal overnutrition establishes a persistent epigenetic “memory” in hypothalamic and metabolic tissues. Altered DNA methylation and chromatin structure in genes encoding key regulators of appetite and hormone signaling (for example, POMC, NPY, MC4R, LEPR, and INSR) provide a mechanistic link between adverse maternal diets, impaired leptin and insulin sensitivity, miswiring of hypothalamic energy-balance circuits, and lifelong susceptibility to obesity and type 2 diabetes.

3. Maternal Undernutrition and the Hypothalamus

Maternal undernutrition encompasses several forms of inadequate nutrient intake, including global energy restriction, low-protein or essential amino acid–deficient diets, and specific micronutrient deficiencies such as zinc, iron, or folate (86). This global imbalance in nutrient availability affects millions of women of reproductive age and represents a core component of the DOHaD framework, which posits that early-life environmental factors, particularly nutrition, shape long-term health trajectories (86). The effects of maternal undernutrition can begin before conception and extend throughout gestation and lactation, with the timing, duration, and severity of nutrient deficits critically determining the nature of fetal and neonatal adaptations (12,14).

Human famine studies, such as the Dutch Hunger Winter and the Leningrad Siege, provide compelling evidence that maternal food deprivation during pregnancy increases the risk of metabolic and cardiovascular disorders in adult offspring, including adiposity, glucose intolerance, and hypertension (14,70). Complementary animal studies have been essential for dissecting mechanisms. In rodent models, maternal global caloric restriction (e.g., approximately 30% of normal intake from embryonic day 10.5 to birth) and maternal protein restriction paradigms consistently demonstrate that nutrient limitation during pregnancy can program offspring for obesity and metabolic dysfunction, whereas restriction limited to lactation does not always produce the same phenotype (86).

Maternal undernutrition perturbs fetal development through several interrelated pathways. First, it compromises the placenta’s fetal nutrient supply axis, and since the placenta regulates the timed delivery of oxygen and nutrients, including those essential for brain development, such disturbances are particularly detrimental to the developing central nervous system (86). Second, undernutrition modifies maternal and placental endocrine systems, altering levels of hormones such as insulin, IGF, and glucocorticoids, which in turn reshape fetal endocrine development, somatic growth, and organogenesis (70). Third, these changes collectively create an adverse intrauterine environment that elicits permanent structural and functional adaptations in key fetal organs, adaptations that may enhance survival under poor postnatal conditions but increase the risk of adult disease when postnatal environments are nutrient-rich (87). Consistent with this, clinical and epidemiological studies show that maternal undernutrition leading to low birth weight is associated with elevated adult susceptibility to hypertension, stroke, and metabolic syndrome (70).

Maternal micronutrient deficiencies, particularly of iron, folate, zinc, vitamin B12, and choline, represent additional layers of undernutrition that can program offspring brain and hypothalamic development (75,88,89). During gestation and lactation, these deficiencies impair placental structure and function, altering angiogenesis, transporter expression, and blood flow, which reduces the delivery of oxygen and critical nutrients to the fetal brain (88). In experimental models, iron deficiency disrupts oligodendrocyte maturation, myelination, and monoaminergic neurotransmitter synthesis, while folate and vitamin B12 deficiency impair one-carbon metabolism, DNA synthesis, and methylation reactions, increasing neuronal apoptosis and leading to long-term cognitive and behavioral alterations (89–92). Zinc deficiency has been shown to interfere with neurogenesis, synaptic plasticity, and antioxidant defense systems, whereas choline insufficiency compromises membrane phospholipid composition, cholinergic neurotransmission, and hippocampal neurogenesis (93). However, much of the existing evidence derives from studies focusing on broader brain regions such as the hippocampus and cortex, rather than the hypothalamus specifically. These findings should therefore be interpreted as hypothesis-generating with respect to hypothalamic developmental programming. Given the high rates of neurogenesis, axon outgrowth, and synapse formation in ARH and PVN nuclei during late gestation and early postnatal life micronutrient deficiencies may plausibly influence several hypothalamic endpoints (7,21,94). Limited preclinical evidence suggests that specific micronutrient deficiencies can alter hypothalamic neuropeptide expression and hormone receptor signaling, but detailed data linking isolated iron, folate, zinc, B12, or choline deficits to changes in NPY/POMC neurons or leptin, insulin, and GLP-1 receptors remain scarce (16,66,76). Thus, micronutrient deficiencies should be considered important but understudied contributors to hypothalamic developmental programming within the broader spectrum of maternal undernutrition (7,88).

Maternal undernutrition significantly influences hypothalamic development and function in offspring, producing long-lasting alterations that lead to metabolic dysregulation (66,95). The developing hypothalamus is particularly susceptible during critical phases of plasticity in both prenatal and early postnatal stages, wherein disruptions in the metabolic and hormonal milieu can permanently alter neural circuitry (16). Experimental models primarily in mice and rats exposed to global caloric restriction or low-protein diets have been central to elucidating these mechanisms (94,96,97).

Maternal undernutrition disrupts the development of key hypothalamic circuits, particularly within the ARH, which houses anorexigenic neurons and orexigenic neurons. In male rat pups, perinatal undernutrition markedly reduces POMC expression and alters ARH wiring, indicating impaired anorexigenic signaling (66). Low-protein maternal diets decrease the number of NPY-immunopositive cells in the ARH and reduce galanin-positive neuron density in the PVN of weanling offspring (96). The density of AgRP-immunoreactive fibers innervating the PVN is similarly downregulated in undernourished pups, and altered hypothalamic mRNA levels of GHSR, AgRP, and POMC have been reported, which may reflect feedback responses or shifts in neuronal cell numbers due to fetal programming (98). These findings highlight the particular vulnerability of ARH projections to the PVN, DMH, and LHA during the developmental window when these long-range connections are being established (17,18). Persistent impairment of melanocortin pathways, including POMC-derived α-MSH signaling via MC4R, suggests limited capacity of the central nervous system to compensate for early structural defects (17,99).

Beyond neuronal populations, maternal undernutrition also affects glial maturation and may contribute to neuroinflammatory processes. Although most evidence for hypothalamic inflammation and gliosis comes from maternal overnutrition models (18,100), glial cells, microglia and astrocytes, are essential for normal neurodevelopment, including synaptogenesis and pruning, regulation of apoptosis, and CNS vascularization (101). Microenvironmental disturbances caused by nutritional imbalance can drive pathological glial activation and low-grade neuroinflammation, which in turn disrupt neuronal connectivity and synaptic function (100).

Maternal undernutrition also impacts cellular nutrient-sensing and stress pathways in the hypothalamus. Protein deprivation significantly alters hypothalamic mechanistic target of rapamycin (mTOR) signaling, a key regulator of feeding behavior that integrates hormonal and nutrient cues (97). Offspring exposed to maternal protein restriction show abnormal hypothalamic mTOR responses to fasting and refeeding, with altered patterns of phosphorylated ribosomal protein S6 (rpS6) and mTOR immunostaining across nuclei such as the ventromedial hypothalamus, ARH, and PVN (97). In parallel, mitochondrial dysfunction particularly defects in oxidative phosphorylation and increased oxidative stress in the hypothalamus, have been implicated as mechanism by which maternal protein imbalance and undernutrition disturb energy homeostasis and feeding behavior (18,102).

The timing and degree of nutritional restriction are crucial determinants of the resulting hypothalamic phenotype. Undernutrition during gestation versus lactation can produce markedly different outcomes, with the perinatal period representing particularly sensitive window for programming (14,66). Maternal undernutrition is thus associated with long-term hypothalamic programming that predisposes to obesity and metabolic disorders (66,96).

3.1. Impact of Maternal Undernutrition on Hypothalamic Hormonal Signaling

This section focuses on the perturbation of key hormonal pathways by maternal undernutrition, emphasizing contrasts with the patterns observed in maternal overnutrition.

3.1.1. Leptin

Maternal undernutrition significantly impacts leptin signaling, a critical regulator of appetite and energy balance. Studies in male rat pups exposed to maternal perinatal undernutrition, specifically a 50% food-restricted diet during gestation and lactation, demonstrate a drastic reduction in the postnatal surge of plasma leptin (66). For example, plasma leptin levels peaked at 0.93 ± 0.23 ng/ml at postnatal day 7 in FR50 pups, compared to 5.17 ± 0.53 ng/ml at PND10 in control animals (66). This contrasts sharply with maternal obesity models, which typically show an amplified and prolonged leptin surge. The diminished neonatal leptin surge in undernourished offspring is associated with disturbances in hypothalamic wiring and the gene expression of anorexigenic POMC neurons (66). Maternal prenatal undernutrition can also lead to a decrease in hypothalamic LepR mRNA levels (6). In some maternal obesity models that paradoxically show low neonatal leptin, reduced early leptin levels are linked to downregulation of LepRb and its downstream signaling mediator, SOCS3, in the hypothalamus at birth (44). This indicates a compromised ability of the hypothalamus to respond to leptin signals.

Maternal undernutrition results in an altered hypothalamic response to leptin and a reduced anorectic effect (16). While early overnutrition (relevant for comparative understanding) can induce leptin resistance in ARH-POMC neurons and alter synaptic signaling (103), leading to hyperphagia and obesity (12), undernutrition similarly disrupts the proper development of these pathways. Leptin is vital for normal energy balance regulation and hypothalamic function, and maintaining its correct levels during neonatal life is crucial for proper neurodevelopment (16).

3.1.2. Insulin

Maternal undernutrition has enduring impacts on the insulin and insulin-like growth factor signaling pathway in offspring, leading to sustained disturbances in metabolic homeostasis. Limited nutrient availability in utero has been shown to modify fetal glucose and insulin metabolism. Studies have demonstrated that intrauterine nutritional restriction alters pancreatic expression of ghrelin and insulin in neonatal rats, thereby linking low birth weight to increased diabetes risk in adulthood (104). Sex-specific differences have been observed, with male offspring from undernourished dams frequently displaying increased plasma insulin levels compared to controls, whereas female offspring appear generally unaffected (12). This sexually dimorphic response indicates that maternal nutritional status may differentially influence endocrine function based on fetal sex. At the central level, prenatal undernutrition has been linked to heightened production of InsR mRNA in the hypothalamus (6), although this upregulation does not inherently improve insulin sensitivity. In fact, animal models that show central resistance to insulin and leptin have lower amounts of downstream signaling mediators such as the InsR-β subunit, PI3-k and Akt in the hypothalamus (20). These molecular alterations correlate with diminished insulin tolerance test results, especially in male offspring, substantiating the concept that increased insulin levels may coexist with diminished insulin sensitivity, a characteristic of insulin resistance (12). At clinical level, limiting nutrients in pregnant women has been demonstrated to slow down the production of fatty acids and make insulin less effective at the tissue level (70).

In addition to molecular modifications, behavioral and physiological effects have also been documented. Offspring exposed to early undernutrition may demonstrate impaired glucose tolerance driven by reduced glucose-stimulated insulin secretion rather than canonical insulin resistance (6). These animals frequently have increased food intake, increased weight gain, and decreased insulin sensitivity, characteristics of a thrifty phenotype. For instance, aged female offspring from nutrient-restricted ewes exhibit increased eating rates, enhanced feed efficiency, higher insulin production, and reduced insulin responsiveness relative to controls (15). Caloric restriction and protein deficit during pregnancy also contribute to this risk by programming long-term alterations in energy regulation and neuroendocrine signaling (21).

3.1.3. GLP-1

Compared with leptin and insulin, the impact of maternal undernutrition on offspring GLP-1 signaling is poorly defined. Classical models of perinatal global calorie restriction or low-protein diets demonstrate marked changes in offspring glucose tolerance, insulin secretion and hypothalamic neurocircuitry, but they rarely report GLP-1 concentrations or GLP-1 receptor expression in the offspring brain(6,13). To date, one maternal perinatal food-restriction model has shown that treatment with the GLP-1 receptor agonist liraglutide attenuates hippocampal microglial activation and pro-inflammatory cytokine expression in male rat pups, suggesting a potential neuroprotective action of GLP-1R activation after early-life nutritional stress rather than a clearly defined defect in endogenous GLP-1 pathways (75). On current evidence, it is therefore not possible to define a consistent pattern of GLP-1 dysregulation following maternal undernutrition, and the consequences for hypothalamic GLP-1 signaling remain an important gap for future research. Future studies should address this gap more directly by measuring maternal and offspring circulating GLP-1 concentrations, hypothalamic and brainstem GLP-1R expression, and downstream central responsiveness to GLP-1R stimulation during critical developmental windows. In particular, studies are needed to determine whether maternal undernutrition alters GLP-1-sensitive pathways in the ARH, PVH, and dorsal vagal complex, including potential effects on vagal afferent input, brainstem GLP-1-producing neurons, microglial activation, and maturation of hypothalamic feeding circuits. Experimental approaches combining maternal undernutrition models with GLP-1R agonist or antagonist administration, together with region-specific analyses of neuronal activation and offspring metabolic phenotyping, would help clarify whether disrupted GLP-1 signaling contributes causally to hypothalamic programming under conditions of nutrient deprivation.

3.2. Epigenetic alterations associated with maternal undernutrition

Although the evidence is more limited than for maternal overnutrition, several models show that maternal undernutrition induces epigenetic changes in hypothalamic genes regulating energy balance. In sheep, periconceptional undernutrition from 60 days before to 30 days after mating leads to marked hypomethylation of the Pomc promoter (approximately 60% reduction) and the glucocorticoid receptor (Gr) promoter (approximately 50% reduction) in fetal hypothalamus, together with increased H3K9 acetylation at these loci and higher Gr mRNA expression, while Pomc and Npy mRNA remain unchanged (99,105). These effects are specific to the hypothalamus and are not observed at unrelated loci such as Oct4 or in other brain regions, indicating gene- and tissue-selective programming (99,105). Follow-up work reports reduced DNA methyltransferase activity and additional changes in histone marks, including altered H3K9ac and H3K27me3 at Pomc and Gr, reinforcing the sensitivity of these pathways to early nutrient scarcity (35,99). Rodent prenatal undernutrition and low-protein models similarly show long-lasting changes in Pomc neuron responsiveness to metabolic cues in the ARH, consistent with durable programming of melanocortin tone, although direct hypothalamic methylation and histone data in these models remain limited (99,105).

4. Conclusion

Maternal nutrition is a central influence on the developmental origin of metabolic disease. This review synthesized evidence from human cohorts and animal studies to demonstrate that both maternal overnutrition and maternal undernutrition program the developing hypothalamus, a key brain region responsible for controlling appetite, energy use, and glucose regulation. Across many models, disturbed leptin and insulin environments during sensitive periods of gestation and early postnatal life alter the maturation of hypothalamic nuclei such as the ARH and PVN. These changes involve altered signaling through leptin, insulin, and in some cases GLP-1, changes in POMC and NPY/AgRP pathways, neuroinflammation, glial and vascular dysfunction, and stable epigenetic modifications in genes such as POMC, NPY, MC4R, LepRb and Insr. Both forms of maternal malnutrition ultimately promote hypothalamic profiles that favour positive energy balance and glucose dysregulation (Figure 1).

Figure 1. Schematic figure of maternal nutrition–induced hypothalamic programming and offspring metabolic outcomes.

Maternal overnutrition (high-fat/Western diets) and undernutrition (caloric, protein and micronutrient restriction) alter the intrauterine environment, disrupting leptin, insulin and GLP-1 signaling, hypothalamic neural circuits, glial activation and epigenetic marks in key genes. These programmed changes in the developing hypothalamus promote altered appetite regulation and increased risk of obesity, type 2 diabetes and cardiometabolic disease in offspring.

The available data also show that the pattern of hypothalamic programming depends on the quality of the maternal diet, the timing and duration of exposure, and the biological sex of the offspring. Findings in this field should be interpreted in light of substantial heterogeneity across studies. Differences in exposure window (preconception, gestation, or lactation), nutritional model (eg, high-fat diet, Western diet, high-sugar diet, calorie restriction, protein restriction, or micronutrient deficiency), species, offspring sex, and age at assessment can all influence the direction and magnitude of hypothalamic and metabolic outcomes. Recognizing these sources of variability is important for interpreting apparently inconsistent findings and for distinguishing shared mechanisms from model-specific effects. These study-level differences and their translational implications are summarized in Table 2.

Table 2.

Summary of studies on the effects of maternal nutrition on offspring hypothalamic programming and metabolic health

Maternal Overnutrition
Model (Species / Human Cohort)	Dietary or Clinical Exposure	Timing of Exposure	Sex	Key Central Hypothalamic Outcome	Reference
Mouse (C57BL/6J)	Maternal obesity	Gestation	Both	Impaired formation of POMC and AgRP projections to hypothalamic target sites, consistent with altered neurocircuit development. Increased blood-brain barrier permeability in the arcuate nucleus of offspring.	Vogt et al., 2014; Kim et al., 2016 (17; 25)
Mouse (C57BL/6J)	Maternal obesogenic diet (45% kcal fat) plus sweetened condensed milk	Gestation	Both	Fetal hypothalamic insulin resistance with reduced expression of proliferative genes and disrupted feeding-pathway development.	Dearden et al., 2020 (19)
Mouse (C57BL/6J)	Maternal HFD (46% calories from fat; 18% protein; 36% carbohydrate)	Gestation / Lactation	Both	Higher AgRP mRNA, reduced Mash1-labeled cells, and increased NPY-neuron population in offspring hypothalamus.	Lemes et al., 2018 (41)
Mouse (C57BL/6J)	Maternal HFHS diet (58 kcal% fat)	Gestation / Lactation	Both	Elevated hypothalamic ER stress, disrupted melanocortin-circuit development, altered POMC signaling, and increased leptin resistance.	Park et al., 2020 (48)
Mouse (C57BL/6J)	Maternal HFD during lactation (45% kcal fat; 20% protein; 35% carbohydrate)	Lactation	Both	Impaired hypothalamic neurogenesis and increased NPY:POMC ratio, with stronger later obesity susceptibility in male offspring.	Xu et al., 2023 (43)
Rat	Maternal overnutrition	Gestation / Lactation	Offspring not clearly specified	Epigenetic changes in regulatory regions of hypothalamic Pomc in offspring.	Ramamoorthy et al., 2018 (21)
Rat (Sprague-Dawley)	Maternal HFD (43.5% calories from fat)	Preconception / Gestation / Lactation	Female	Higher hypothalamic NPY mRNA and lower POMC mRNA, indicating dysregulated hypothalamic appetite signaling.	Nguyen et al., 2017 (42)
Rat (Wistar)	Maternal HFD	Lactation	Both	Hypothalamic leptin resistance with altered leptin-dependent STAT3 signaling in offspring	Férézou-Viala et al.,2007 (8)
Human cohort	Gestational diabetes mellitus diagnosed before 26 weeks	Gestation	Both	Evidence of mediobasal hypothalamic gliosis in exposed children.	Chandrasekaran et al., 2022 (54)
Human cohort	Maternal diabetes or hypertension	Gestation	Both	Childhood hypothalamic gliosis detected by MRI in exposed children.	Olerich et al., 2024 (55)
Maternal Undernutrition
Mouse	Maternal undernutrition / 30% food restriction	Gestation / Lactation	Both	Upregulation of hypothalamic Ghsr mRNA and increased AgRP and POMC mRNA in undernourished pups.	Sun et al., 2020 (98)
Mouse (Balb/c)	Maternal undernutrition / 50% food restriction during the last week of gestation	Late gestation	Both	Increased hypothalamic leptin receptor (Ob-Rb) expression in offspring after maternal caloric restriction.	Manuel-Apolinar et al., 2010 (9)
Rat (Wistar)	Maternal low-protein diet (8% protein; control 17% protein)	Gestation / Lactation	Male	Lower number and percentage of NPY-positive neurons in the arcuate nucleus, with malformed hypothalamic nuclei in offspring.	Plagemann et al., 2000 (96)
Rat	Maternal perinatal undernutrition / 50% food-restricted diet	Gestation / Lactation	Male	Reduced hypothalamic POMC expression and disrupted POMC projections to the PVN in offspring.	Delahaye et al., 2008 (65)

High-fat and high-sugar diets with maternal obesity tend to exaggerate or prolong the neonatal leptin surge, promote central leptin and insulin resistance, and produce lasting increases in body weight and glucose intolerance. In contrast, global energy restriction and low protein diets often blunt the leptin surge, impair normal hypothalamic development, and disturb insulin and insulin-like growth factor signaling, with several studies reporting sex specific effects. Some work suggests that deficiencies of micronutrients such as iron, folate, and zinc may further modify these outcomes, but their specific impact on hypothalamic circuits is less well defined and remains an emerging area. Despite these advances, this review is limited by the fact that most mechanistic evidence comes from rodent models. In contrast, direct human data on hypothalamic development, circuitry, and hormone responsiveness remain limited. Human studies are largely observational and rely on indirect markers, making it difficult to establish causality or fully translate animal findings to clinical settings.

These gaps define clear priorities for future research. In particular, there is an urgent need for well-designed longitudinal human studies that integrate maternal nutritional exposures with hormonal, imaging, and metabolic assessments across pregnancy, infancy, and later life. Such studies will be essential to validate mechanistic insights derived from animal models, improve translational relevance, and inform targeted interventions for maternal and offspring metabolic health. Experimental work should examine nutrient-specific and time-specific effects on defined neuronal and glial populations within individual hypothalamic nuclei and identify which epigenetic marks are causal in driving long-term dysfunction. The GLP-1 system in models of maternal undernutrition is still poorly characterized and needs direct study at the level of secretion, receptor expression, and central responsiveness. The contribution of isolated micronutrient deficiencies to hypothalamic development and hormone sensitivity also requires more systematic investigation. A better definition of critical windows and the degree of reversibility of programming, including the potential of early nutritional or hormonal interventions to restore healthier hypothalamic function, will be important for designing realistic preventive strategies. Together, these efforts can support preconception and antenatal care that promotes healthy maternal weight, balanced macronutrient intake, and adequate micronutrient status, to reduce intergenerational transmission of metabolic disease risk.

Data availability:

This review does not involve original research or new datasets.