A systematic review and meta-analysis of the effect of obesity on patients undergoing lower extremity revascularization.

OBJECTIVE: In the present review, we assessed the effect of obesity on clinical outcomes for patients with peripheral arterial disease who had undergone endovascular or open lower extremity revascularization surgery. METHODS: A systematic search strategy of MEDLINE, EMBASE, CINAHL, Web of Science, and Cochrane Library was conducted. The included studies had compared obese and nonobese cohorts with peripheral arterial disease who had undergone endovascular or open lower extremity revascularization. The outcomes included mortality, major adverse cardiovascular events, major adverse limb events, surgical site infections, endovascular access site complications, and perioperative complications. RESULTS: Eight studies were included with 171,648 patients. The obese patients (body mass index ≥30 kg/m2) were more likely to be women, to have diabetes, and to have more cardiovascular comorbidities despite being younger. No association was found between obesity and peripheral arterial disease severity. Obesity was associated with an overall 22% decreased mortality risk after lower extremity revascularization (risk ratio [RR], 0.78; 95% confidence interval [CI], 0.71-0.85; P < .001; I2 = 0%; GRADE (grading of recommendations assessment, development, evaluation), very low quality). A subgroup analysis by intervention type showed similar findings (endovascular: RR, 0.79; 95% CI, 0.71-0.87; P < .001; I2 = 0%; open: RR, 0.70; 95% CI, 0.51-0.95; P = .024; I2 = 43%). Obesity was associated with a 14% decreased risk of major adverse cardiovascular events for open surgery only (RR, 0.86; 95% CI, 0.76-0.98; P = .021; I2 = 0%; GRADE, very low quality). Obesity was associated with an increased risk of surgical site infections pooled across intervention types (RR, 1.69; 95% CI, 1.34-2.14; P < .001; I2 = 78%; GRADE, very low quality). No association was found between obesity and major adverse limb events (RR, 1.02; 95% CI, 0.93-1.11; P = .73; I2 = 15%; GRADE, very low quality) or endovascular access site complications (RR, 1.11; 95% CI, 0.76-1.63; P = .58; I2 = 86%; GRADE, very low quality). Pooled perioperative complications did not differ between the obese and nonobese cohorts (RR, 1.04; 95% CI, 0.84-1.28; P = .73; I2 = 92%; GRADE, very low quality). CONCLUSIONS: Obesity was associated with reduced mortality risk with both endovascular and open surgery, although a reduction in major adverse cardiovascular events was only observed with open surgery. In addition, obese patients had an increased risk of surgical site infections. Obesity was not associated with major adverse limb events, endovascular access site complications, or perioperative complications. The GRADE quality of evidence was very low. The findings from the present review suggest a survival advantage for obese patients with peripheral arterial disease. Future studies could focus on prospectively investigating the effect of obesity on peripheral arterial disease outcomes. A nuanced evaluation of body mass index as a preoperative risk factor is warranted.

Comorbid Depression is Associated with Increased Major Adverse Limb Events in Peripheral Arterial Disease: A Systematic Review and Meta-analysis.

OBJECTIVE: Depression is a significant risk factor for death in coronary artery disease. Conversely, the research surrounding depression and peripheral arterial disease is limited. This review aimed to systematically evaluate the available literature on the impact of comorbid depression on adverse outcomes in peripheral arterial disease. DATA SOURCES: A systematic review and meta-analysis were performed using the following databases MEDLINE, EMBASE, CINAHL, PsycINFO, and Cochrane Library from inception until July 2021. REVIEW METHODS: Included studies compared depressed and non-depressed patients with peripheral arterial disease. The outcomes included death, major adverse cardiovascular events, and major adverse limb events. RESULTS: A total of 9 297 articles were searched. Of these, seven studies were identified. Depressed patients were more likely to be women, diabetic, have a history of smoking, and have chronic limb threatening ischaemia, despite being younger than non-depressed patients. There was a 20% increase in major adverse limb events in depressed patients (RR 1.20, 95% CI 1.11 - 1.31, z = 3.9, p < .001, GRADE strength: very low) but no increased risk of death (RR 1.03, 95% CI 0.72 - 1.40, z = 0.06, p = .95, GRADE strength: very low) or major adverse cardiovascular events (RR 1.16, 95% CI 0.67 - 2.01, z = 0.54, p = .59, GRADE strength: very low). A follow up meta-regression of various comorbidities and demographic variables did not demonstrate a significant contribution to the observed risk ratio for major adverse limb events. CONCLUSION: Depression was reported in 13% of patients with peripheral arterial disease, associated with more medical comorbidity, and a 20% increased risk of major adverse limb events. Although the strength of this evidence is very low, the current state of the literature remains limited. Future studies should prospectively assess the impact of depression and its relationship to medical comorbidities and high risk health behaviours.

Nutritional manipulations in the perinatal period program adipose tissue in offspring.

Epidemiological studies demonstrated initially that maternal undernutrition results in low birth weight with increased risk for long-lasting energy balance disorders. Maternal obesity and diabetes associated with high birth weight, excessive nutrition in neonates, and rapid catchup growth also increase the risk of adult-onset obesity. As stated by the Developmental Origin of Health and Disease concept, nutrient supply perturbations in the fetus or neonate result in long-term programming of individual body weight set point. Adipose tissue is a key fuel storage unit involved mainly in the maintenance of energy homeostasis. Studies in numerous animal models have demonstrated that the adipose tissue is the focus of developmental programming events in a sex- and depot-specific manner. In rodents, adipose tissue development is particularly active during the perinatal period, especially during the last week of gestation and during early postnatal life. In contrast to rodents, this process essentially takes place before birth in bigger mammals. Despite these different developmental time windows, altricial and precocial species share several mechanisms of adipose tissue programming. Offspring from malnourished dams present adipose tissue with a series of alterations: impaired glucose uptake, insulin and leptin resistance, low-grade inflammation, modified sympathetic activity with reduced noradrenergic innervations, and thermogenesis. These modifications reprogram adipose tissue metabolism by changing fat distribution and composition and by enhancing adipogenesis, predisposing the offspring to fat accumulation. Subtle adipose tissue circadian rhythm changes are also observed. Inappropriate hormone levels, modified tissue sensitivity (especially glucocorticoid system), and epigenetic mechanisms are key factors for adipose tissue programming during the perinatal period.

Maternal calorie restriction modulates placental mitochondrial biogenesis and bioenergetic efficiency: putative involvement in fetoplacental growth defects in rats.

Low birth weight is associated with an increased risk for developing type 2 diabetes and metabolic diseases. The placental capacity to supply nutrients and oxygen to the fetus represents the main determiner of fetal growth. However, few studies have investigated the effects of maternal diet on the placenta. We explored placental adaptive proteomic processes implicated in response to maternal undernutrition. Rat term placentas from 70% food-restricted (FR30) mothers were used for a proteomic screen. Placental mitochondrial functions were evaluated using molecular and functional approaches, and ATP production was measured. FR30 drastically reduced placental and fetal weights. FR30 placentas displayed 14 proteins that were differentially expressed, including several mitochondrial proteins. FR30 induced a marked increase in placental mtDNA content and changes in mitochondrial functions, including modulation of the expression of genes implicated in biogenesis and bioenergetic pathways. FR30 mitochondria showed higher oxygen consumption but failed to maintain their ATP production. Maternal undernutrition induces placental mitochondrial abnormalities. Although an increase in biogenesis and bioenergetic efficiency was noted, placental ATP level was reduced. Our data suggest that placental mitochondrial defects may be implicated in fetoplacental pathologies.

Neonatal hyperoxia leads to white adipose tissue remodeling and susceptibility to hypercaloric diet.

Individuals born preterm are at higher risk of cardiovascular and metabolic diseases in adulthood, through mechanisms not completely understood. White adipose tissue in humans and rodents is a dynamic endocrine organ and a critical player in the regulation of metabolic homeostasis. However, the impact of preterm birth on white adipose tissue remains unknown. Using a well-established rodent model of preterm birth-related conditions in which newborn rats are exposed during postnatal days 3-10 to 80% of oxygen, we evaluated the impact of transient neonatal hyperoxia on adult perirenal white adipose tissue (pWAT) and liver. We further assessed the effect of a second hit with a high-fat high-fructose hypercaloric diet (HFFD). We evaluated 4-month-old adult male rats after 2 months of HFFD. Neonatal hyperoxia led to pWAT fibrosis and macrophage infiltration without modification in body weight, pWAT weight, or adipocyte size. In animals exposed to neonatal hyperoxia vs. room air control, HFFD resulted in adipocyte hypertrophy, lipid accumulation in the liver, and increased circulating triglycerides. Overall, preterm birth-related conditions had long-lasting effects on the composition and morphology of pWAT, along with a higher susceptibility to the deleterious impact of a hypercaloric diet. These changes suggest a developmental pathway to long-term metabolic risk factors observed clinically in adults born preterm through programming of white adipose tissue.

Maternal prenatal undernutrition programs adipose tissue gene expression in adult male rat offspring under high-fat diet.

Several studies have shown that maternal undernutrition leading to low birth weight predisposes offspring to the development of metabolic pathologies such as obesity. Using a model of prenatal maternal 70% food restriction diet (FR30) in rat, we evaluated whether postweaning high-fat (HF) diet would amplify the phenotype observed under standard diet. We investigated biological parameters as well as gene expression profile focusing on white adipose tissues (WAT) of adult offspring. FR30 procedure does not worsen the metabolic syndrome features induced by HF diet. However, FR30HF rats displayed catch-up growth to match the body weight of adult control HF animals, suggesting an increase of adiposity while showing hyperleptinemia and a blunted increase of corticosterone. Using quantitative RT-PCR array, we demonstrated that FR30HF rats exhibited leptin and Ob-Rb as well as many peptide precursor and receptor gene expression variations in WAT. We also showed that the expression of genes involved in adipogenesis was modified in FR30HF animals in a depot-specific manner. We observed an opposite variation of STAT3 phosphorylation levels, suggesting that leptin sensitivity is modified in WAT adult FR30 offspring. We demonstrated that 11ß-HSD1, 11ß-HSD2, GR, and MR genes are coexpressed in WAT and that FR30 procedure modifies gene expression levels, especially under HF diet. In particular, level variation of 11ß-HSD2, whose protein expression was detected by Western blotting, may represent a novel mechanism that may affect WAT glucocorticoid sensitivity. Data suggest that maternal undernutrition differently programs the adult offspring WAT gene expression profile that may predispose for altered fat deposition.

Maternal perinatal undernutrition programs a "brown-like" phenotype of gonadal white fat in male rat at weaning.

Several studies indicate that maternal undernutrition sensitizes the offspring to the development of metabolic disorders, such as obesity. Using a model of perinatal maternal 50% food-restricted diet (FR50), we recently reported that rat neonates from undernourished mothers exhibit decreased leptin plasma levels associated with alterations of hypothalamic proopiomelanocortin system. The present study aimed at examining the consequences of FR50 on the brain-adipose axis in male rat neonates. Using quantitative RT-PCR array containing 84 obesity-related genes, we demonstrated that most of the genes involved in energy metabolism regulation are expressed in rat gonadal white adipose tissue (WAT) and are sensitive to maternal perinatal undernutrition (MPU). In contrast, hypothalamic gene expression was not substantially affected by MPU. Gene expression of uncoupling protein 1 (UCP1), a marker of brown adipocytes, showed an almost 400-fold stimulation in postnatal day 21 (PND21) FR50 animals, suggesting that their gonadal WAT possesses a brown-like phenotype. This was confirmed by histological and immunoshistochemical procedures, which demonstrated that PND21 FR50 gonadal adipocytes are multilocular, resembling those present in interscapular brown adipose tissue, and exhibit an overexpression of UCP1 and neuropeptide Y (NPY) at the protein level. Control animals contained almost exclusively "classical" unilocular white adipocytes that did not show high UCP1 and NPY labeling. After weaning, FR50 animals exhibited a transient hyperphagia that was associated with the disappearance of brown-like fat pads in PND30 WAT. Our results demonstrate that MPU delays the maturation of gonadal WAT during critical developmental time windows, suggesting that it could have long-term consequences on body weight regulation in the offspring.

Kidney Size, Renal Function, Ang (Angiotensin) Peptides, and Blood Pressure in Young Adults Born Preterm.

Preterm birth incurs a higher risk for adult cardiovascular diseases, including hypertension. Because preterm birth may impact nephrogenesis, study objectives were to assess renal size and function of adults born preterm versus full term and to examine their relationship with blood pressure (BP; 24-hour ambulatory BP monitoring) and circulating renin-Ang (angiotensin) system peptides. The study included 92 young adults born (1987-1997) preterm (≤29 weeks of gestation) and term (n=92) matched for age, sex, and race. Young adults born preterm had smaller kidneys (80±17 versus 90±18 cm3/m2; P<0.001), higher urine albumin-to-creatinine ratio (0.70; interquartile range, 0.47-1.14 versus 0.58, interquartile range 0.42 to 0.78 mg/mmol, P=0.007), higher 24-hour systolic (121±9 versus 116±8 mm Hg; P=0.001) and diastolic (69±5 versus 66±6 mm Hg; P=0.004) BP, but similar estimated glomerular filtration rate. BP was inversely correlated with kidney size in preterm participants. Plasma Ang I was higher in preterm versus term participants (36.3; interquartile range, 13.2-62.3 versus 19.4; interquartile range, 9.9-28.1 pg/mL; P<0.001). There was no group difference in renin, Ang II, Ang (1-7), and alamandine. In the preterm, but not in the term group, higher BP was significantly associated with higher renin and alamandine and lower birth weight and gestational age with smaller adult kidney size. Young adults born preterm have smaller kidneys, higher urine albumin-to-creatinine ratio, higher BP, and higher circulating Ang I levels compared with term controls. Preterm young adults with smaller kidneys have higher BP. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT03261609.

Age- and sex-related changes in rat renal function and pathology following neonatal hyperoxia exposure.

Preterm neonates are prematurely exposed to high oxygen levels at birth which may adversely impact ongoing renal development. The aim of this study was to determine the effects of neonatal hyperoxia exposure on renal function and morphology with aging. Sprague Dawley rat pups were raised in a hyperoxic environment (80% oxygen) from P3 to P10 during ongoing postnatal nephrogenesis. Control litters were kept in room air (n = 6-8 litters/group; one male, one female/litter/age). Kidney function (urine and plasma creatinine, sodium, and protein) and morphology (renal corpuscle size, glomerulosclerosis, fibrosis, and glomerular crescents) were assessed at 1, 5, and 11 months of age. Neonatal hyperoxia exposure had no impact on body or kidney weights. Creatinine clearance was significantly reduced following hyperoxia exposure at 5 months; there was no significant effect on renal function at 1 or 11 months. The percentage of crescentic glomeruli (indicative of glomerular injury) was markedly increased in 11 month hyperoxia-exposed males. Renal corpuscle size, glomerulosclerosis index, and renal fibrosis were not affected. Findings suggest that exposure to high oxygen levels during development may impact renal functional capacity and increase susceptibility to renal disease in adulthood depending on age and sex.

Activation of the Cardiac Renin-Angiotensin System in High Oxygen-Exposed Newborn Rats: Angiotensin Receptor Blockade Prevents the Developmental Programming of Cardiac Dysfunction.

Newborn rats exposed to high oxygen (O2), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin-angiotensin system. Cardiac renin-angiotensin system activation in O2-exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin-angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague-Dawley newborn rats were kept with their mother in 80% O2 or room air (control) from days 3 to 10 (P3-P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O2 exposure), P5, P10 (end of O2), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O2-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-ß/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O2 prevents the development of cardiac alterations later in life in rats. These findings highlight the key role of neonatal renin-angiotensin system activation in the developmental programming of cardiac dysfunction induced by deleterious neonatal conditions.

Apelin Controls Fetal and Neonatal Glucose Homeostasis and Is Altered by Maternal Undernutrition.

The adequate control of glucose homeostasis during both gestation and early postnatal life is crucial for the development of the fetoplacental unit and adaptive physiological responses at birth. Growing evidences indicate that apelin and its receptor, APJ, which are expressed across a wide range of tissues, exert important roles in glucose homeostasis in adults. However, little is known about the function of the apelinergic system during gestation. In this study, we evaluated the activity of this system in rats, the role of apelin in fetal and neonatal glucose homeostasis, and its modulation by maternal food restriction. We found that 1) the apelinergic system was expressed at the fetoplacental interface and in numerous fetal tissues, 2) ex vivo, the placenta released high amounts of apelin in late gestation, 3) intravenous apelin injection in mothers increased the transplacental transport of glucose, and 4) intraperitoneal apelin administration in neonates increased glucose uptake in lung and muscle. Maternal food restriction drastically reduced apelinemia in both mothers and growth-restricted fetuses and altered the expression of the apelinergic system at the fetoplacental interface. Together, our data demonstrate that apelin controls fetal and neonatal glucose homeostasis and is altered by fetal growth restriction induced by maternal undernutrition.

The hypothalamic POMC mRNA expression is upregulated in prenatally undernourished male rat offspring under high-fat diet.

Epidemiological studies demonstrated that adverse environmental factors leading to intrauterine growth retardation (IUGR) and low birth weight may predispose individuals to increased risk of metabolic syndrome. In rats, we previously demonstrated that adult male IUGR offspring from prenatal 70% food-restricted dams throughout gestation (FR30) were predisposed to energy balance dysfunctions such as impaired glucose intolerance, hyperleptinemia, hyperphagia and adiposity. We investigated whether postweaning moderate high-fat (HF) diet would amplify the phenotype focusing on the hypothalamus gene expression profile. Prenatally undernourished rat offspring were HF-fed from weaning until adulthood while body weight and food intake were measured. Tissue weights, glucose tolerance and plasma endocrine parameters levels were determined in 4-month-old rats. Hypothalamic gene expression profiling of adult FR30 rat was performed using Illumina microarray analysis and the RatRef-12 Expression BeadChip that contains 21,792 rat genes. Under HF diet, contrary to C animals, FR30 rats displayed increased body weight. However, most of the endocrine disorders observed in chow diet-fed adult FR30 were alleviated. We also observed very few gene expression changes in hypothalamus of FR30 rat. Amongst factors involved in hypothalamic energy homeostasis programming system, only the POMC and transthyretin mRNA expression levels were preferentially increased under HF diet. Both elevated gene expression levels may be seen as adaptive mechanisms counteracting against deleterious effects of HF feeding in FR30 animals. This study shows that the POMC gene expression is a key target of long-term developmental programming in prenatally undernourished male rat offspring, specifically within an obesogenic environment.

Is the adipose tissue a key target of developmental programming of adult adiposity by maternal undernutrition?

Epidemiological studies have shown that maternal undernutrition during pregnancy (MU) leads to intrauterine growth retardation and low birth weight, and may predispose individuals to the development of metabolic syndrome symptoms later in life such as overweight. Some clues from a model of prenatal maternal 70% food-restricted diet throughout gestation in pregnant female rats (FR30) suggest that the white adipose tissue (WAT) is a key target of MU fetal programming. Under standard diet, although showing a lean phenotype, adult FR30 male rats were predisposed to adiposity exhibiting higher serum leptin and corticosterone concentration, two hormones actively involved in WAT regulation. Although FR30 procedure does not worsen the metabolic syndrome features induced by HF diet, FR30HF rats gained more weight and showed hyperleptinemia suggesting increased adiposity. WAT FR30 adult rats revealed marked changes in transcript levels of several genes. In particular, leptin and Ob-Rb, many peptide precursors and receptors, factors involved in lipogenesis and glucocorticoid sensitivity mRNA expression levels as well as mechanisms involved in leptin sensitivity, were modified in FR30 offspring in depot-specific and diet-specific manners. These modifications might predispose for altered fat accumulation in adult male rat offspring.

Do neurotrophins regulate the feto-placental development?

Numerous data highlight the importance of a fine regulation of the fetal growth for the individual's subsequent susceptibility to diseases. Recent evidence suggests that neurotrophins may have important functions during pregnancy and that they could modulate fetal growth. We hypothesize that neurotrophins may participate in fetal growth by different pathways: (1) these molecules may participate in the development and the maturation of both central and peripheral fetal organs, including the placenta; (2) neurotrophins may constitute a link between the maternal nutrition and the fetal nutrients demand and thus could act as a nutrient sensor for the development and efficiency of the placenta; (3) maternal and placental neurotrophins may control the fetal development directly but also by activating the production and release of others growth factors. In conclusion, neurotrophins may participate to a new pathway controlling fetal growth and may be implicated, at least in part, under physiopathological conditions in disturbances of the fetal growth trajectory.

Influence of prenatal undernutrition on the effects of clozapine and aripiprazole in the adult male rats: relevance to a neurodevelopmental origin of schizophrenia?

Epidemiological and experimental data indicate that maternal undernutrition may sensitize the offspring to the apparition of chronic diseases such as metabolic syndrome and schizophrenia, suggesting that these pathologies may have a developmental origin. To test this hypothesis, we have compared the effects of a 4 weeks treatment of clozapine (30 mg/kg once daily, p.o.) or aripiprazole (10 mg/kg once daily, p.o.) on metabolic and hormonal parameters in 4-month-old male animals from control or 70% prenatally food-restricted mothers (FR30 model). Both neuroleptics did not markedly modify body weight gain and food intake in both controls and FR30 rats. Clozapine decreased insulin secretion in both groups but significantly diminished leptin, corticosterone and glucose plasma levels only in FR30 animals. Aripiprazole decreased corticosterone plasma levels only in FR30 animals. Using quantitative RT-PCR array containing 84 obesity-related genes, we identified several genes involved in energy metabolism regulation whose expression was modified by clozapine or aripiprazole in adult male rat hypothalami. In addition, we demonstrated that expression of some of these genes was differentially affected by each neuroleptic in the hypothalamus of both FR30 and control animals. Although no marked metabolic alterations were observed in both control and FR30 animals after clozapine or aripiprazole treatment, our data indicate that offspring from undernourished mothers exhibit a modified sensitivity to atypical neuroleptics. Our results do not rule out a putative developmental origin of schizophrenia and may help to understand the way by which atypical neuroleptics, such as clozapine, sensitize schizophrenic patients to the development of metabolic disorders.

Maternal prenatal undernutrition alters the response of POMC neurons to energy status variation in adult male rat offspring.

Epidemiological studies suggest that maternal undernutrition predisposes the offspring to development of energy balance metabolic pathologies in adulthood. Using a model of a prenatal maternal 70% food-restricted diet (FR30) in rats, we evaluated peripheral parameters involved in nutritional regulation, as well as the hypothalamic appetite-regulatory system, in nonfasted and 48-h-fasted adult offspring. Despite comparable glycemia in both groups, mild glucose intolerance, with a defect in glucose-induced insulin secretion, was observed in FR30 animals. They also exhibited hyperleptinemia, despite similar visible fat deposits. Using semiquantitative RT-PCR, we observed no basal difference of hypothalamic proopiomelanocortin (POMC) and neuropeptide Y (NPY) gene expression, but a decrease of the OB-Rb and an increase of insulin receptor mRNA levels, in FR30 animals. These animals also exhibited basal hypercorticosteronemia and a blunted increase of corticosterone in fasted compared with control animals. After fasting, FR30 animals showed no marked reduction of POMC mRNA levels or intensity of beta-endorphin-immunoreactive fiber projections. By contrast, NPY gene expression and immunoreactive fiber intensity increased. FR30 rats also displayed subtle alterations of food intake: body weight-related food intake was higher and light-dark phase rhythm and refeeding time course were modified after fasting. At rest, in the morning, hyperinsulinemia and a striking increase in the number of c-Fos-containing cells in the arcuate nucleus were observed. About 30% of the c-Fos-expressing cells were POMC neurons. Our data suggest that maternal undernutrition differently programs the long-term appetite-regulatory system of offspring, especially the response of POMC neurons to energy status and food intake rhythm.