Octopamine integrates the status of internal energy supply into the formation of food-related memories.

The brain regulates food intake in response to internal energy demands and food availability. However, can internal energy storage influence the type of memory that is formed? We show that the duration of starvation determines whether Drosophila melanogaster forms appetitive short-term or longer-lasting intermediate memories. The internal glycogen storage in the muscles and adipose tissue influences how intensely sucrose-associated information is stored. Insulin-like signaling in octopaminergic reward neurons integrates internal energy storage into memory formation. Octopamine, in turn, suppresses the formation of long-term memory. Octopamine is not required for short-term memory because octopamine-deficient mutants can form appetitive short-term memory for sucrose and to other nutrients depending on the internal energy status. The reduced positive reinforcing effect of sucrose at high internal glycogen levels, combined with the increased stability of food-related memories due to prolonged periods of starvation, could lead to increased food intake.

Deciding what and how much to eat is a complex biological process which involves balancing many types of information such as the levels of internal energy storage, the amount of food previously available in the environment, the perceived value of certain food items, and how these are remembered. At the molecular level, food contains carbohydrates that are broken down to produce glucose, which is then delivered to cells under the control of a hormone called insulin. There, glucose molecules are either immediately used or stored as glycogen until needed. Insulin signalling is also known to interact with the brain's decision-making systems that control eating behaviors; however, how our brains balance food intake with energy storage is poorly understood. Berger et al. set out to investigate this question using fruit flies as an experimental model. These insects also produce insulin-like molecules which help to relay information about glycogen levels to the brain's decision-making system. In particular, these signals reach a population of neurons that produce a messenger known as octopamine similar to the human noradrenaline, which helps regulate how much the flies find consuming certain types of foods rewarding. Berger et al. were able to investigate the role of octopamine in helping to integrate information about internal and external resource levels, memory formation and the evaluation of different food types. When the insects were fed normally, increased glycogen levels led to foods rich in carbohydrates being rated as less rewarding by the decision-making cells, and therefore being consumed less. Memories related to food intake were also short-lived ­ in other words, long-term 'food memory' was suppressed, re-setting the whole system after every meal. In contrast, long periods of starvation in insects with high carbohydrates resources produced a stable, long-term memory of food and hunger which persisted even after the flies had fed again. This experience also changed their food rating system, with highly nutritious foods no longer being perceived as sufficiently rewarding. As a result, the flies overate. This study sheds new light on the mechanisms our bodies may use to maintain energy reserves when food is limited. The persistence of 'food memory' after long periods of starvation may also explain why losing weight is difficult, especially during restrictive diets. In the future, Berger et al. hope that this knowledge will contribute to better strategies for weight management.

Severe prenatal shocks and adolescent health: Evidence from the Dutch Hunger Winter.

This paper investigates health impacts at the end of adolescence of prenatal exposure to multiple shocks, by exploiting the unique natural experiment of the Dutch Hunger Winter. At the end of World War II, a famine occurred abruptly in the Western Netherlands (November 1944-May 1945), pushing the previously and subsequently well-nourished Dutch population to the brink of starvation. We link high-quality military recruits data with objective health measurements for the cohorts born in the years surrounding WWII with newly digitised historical records on calories and nutrient composition of the war rations, daily temperature, and warfare deaths. Using difference-in-differences and triple differences research designs, we first show that the cohorts exposed to the Dutch Hunger Winter since early gestation have a higher Body Mass Index and an increased probability of being obese at age 18. We then find that this effect is partly moderated by warfare exposure and a reduction in energy-adjusted protein intake. Lastly, we account for selective mortality using a copula-based approach and newly-digitised data on survival rates, and find evidence of both selection and scarring effects. These results emphasise the complexity of the mechanisms at play in studying the consequences of early conditions.

Gut microbiome resilience of green-lipped mussels, Perna canaliculus, to starvation

Host gut microbiomes play an important role in animal health and resilience to conditions, such as malnutrition and starvation. These host-microbiome relationships are poorly understood in the marine mussel Perna canaliculus, which experiences significant variations in food quantity and quality in coastal areas. Prolonged starvation may be a contributory factor towards incidences of mass mortalities in farmed mussel populations, resulting in highly variable production costs and unreliable market supplies. Here, we examine the gut microbiota of P. canaliculus in response to starvation and subsequent re-feeding using high-throughput amplicon sequencing of the 16S rRNA gene. Mussels showed no change in bacterial species richness when subjected to a 14-day starvation, followed by re-feeding/recovery. However, beta bacteria diversity revealed significant shifts (PERMANOVA p-value < 0.001) in community structure in the starvation group and no differences in the subsequent recovery group (compared to the control group) once they were re-fed, highlighting their recovery capability and resilience. Phylum-level community profiles revealed an elevation in dominance of Proteobacteria (ANCOM-BC p-value <0.001) and Bacteroidota (ANCOM-BC p-value = 0.04) and lower relative abundance of Cyanobacteria (ANCOM-BC p-value = 0.01) in the starvation group compared to control and recovery groups. The most abundant genus-level shifts revealed relative increases of the heterotroph Halioglobus (p-value < 0.05) and lowered abundances of the autotroph Synechococcus CC9902 in the starvation group. Furthermore, a SparCC correlation network identified co-occurrence of a cluster of genera with elevated relative abundance in the starved mussels that were positively correlated with Synechococcus CC9902... (AU)

Starvation-resistant cavefish reveal conserved mechanisms of starvation-induced hepatic lipotoxicity.

Starvation causes the accumulation of lipid droplets in the liver, a somewhat counterintuitive phenomenon that is nevertheless conserved from flies to humans. Much like fatty liver resulting from overfeeding, hepatic lipid accumulation (steatosis) during undernourishment can lead to lipotoxicity and atrophy of the liver. Here, we found that although surface populations of Astyanax mexicanus undergo this evolutionarily conserved response to starvation, the starvation-resistant cavefish larvae of the same species do not display an accumulation of lipid droplets upon starvation. Moreover, cavefish are resistant to liver atrophy during starvation, providing a unique system to explore strategies for liver protection. Using comparative transcriptomics between zebrafish, surface fish, and cavefish, we identified the fatty acid transporter slc27a2a/fatp2 to be correlated with the development of fatty liver. Pharmacological inhibition of slc27a2a in zebrafish rescues steatosis and atrophy of the liver upon starvation. Furthermore, down-regulation of FATP2 in Drosophila larvae inhibits the development of starvation-induced steatosis, suggesting the evolutionarily conserved importance of the gene in regulating fatty liver upon nutrition deprivation. Overall, our study identifies a conserved, druggable target to protect the liver from atrophy during starvation.

Metabolic and circadian inputs encode anticipatory biogenesis of hepatic fed microRNAs.

Starvation and refeeding are mostly unanticipated in the wild in terms of duration, frequency, and nutritional value of the refed state. Notwithstanding this, organisms mount efficient and reproducible responses to restore metabolic homeostasis. Hence, it is intuitive to invoke expectant molecular mechanisms that build anticipatory responses to enable physiological toggling during fed-fast cycles. In this regard, we report anticipatory biogenesis of oscillatory hepatic microRNAs that peak during a fed state and inhibit starvation-responsive genes. Our results clearly demonstrate that the levels of primary and precursor microRNA transcripts increase during a fasting state, in anticipation of a fed response. We delineate the importance of both metabolic and circadian cues in orchestrating hepatic fed microRNA homeostasis in a physiological setting. Besides illustrating metabo-endocrine control, our findings provide a mechanistic basis for the overarching influence of starvation on anticipatory biogenesis. Importantly, by using pharmacological agents that are widely used in clinics, we point out the high potential of interventions to restore homeostasis of hepatic microRNAs, whose deregulated expression is otherwise well established to cause metabolic diseases.

Does hypoleptinemia trigger entrapment in anorexia nervosa? Etiological and clinical considerations.

Based on the recent observation that human recombinant leptin (r-Met-hu-leptin; metreleptin) may induce a profound alleviation of the complex symptomatology of patients with anorexia nervosa (AN), we examine the implications for our conceptualisation of this eating disorder. Hypoleptinemia as a core endocrine feature of AN serves as a central and peripheral trigger of tissue-specific adaptations to starvation. In this narrative review, we argue that leptin deficiency may explain many of the puzzling features of this eating disorder. Weight loss can be viewed as a two-step process, with only the second step entailing hypoleptinemia and thereby the entrapment characteristic of AN. We discuss the central and peripheral distribution of leptin receptors and consider possible functional implications of hypoleptinemia. We contrast the slow psychological recovery of patients with AN and of people who experienced starvation upon weight recovery with the rapid onset of improvements upon off-label metreleptin treatment. Characteristics of the sex and age dependent secretion of leptin may contribute to the elevated vulnerability of young females to develop AN.

Polar bear energetic and behavioral strategies on land with implications for surviving the ice-free period.

Declining Arctic sea ice is increasing polar bear land use. Polar bears on land are thought to minimize activity to conserve energy. Here, we measure the daily energy expenditure (DEE), diet, behavior, movement, and body composition changes of 20 different polar bears on land over 19-23 days from August to September (2019-2022) in Manitoba, Canada. Polar bears on land exhibited a 5.2-fold range in DEE and 19-fold range in activity, from hibernation-like DEEs to levels approaching active bears on the sea ice, including three individuals that made energetically demanding swims totaling 54-175 km. Bears consumed berries, vegetation, birds, bones, antlers, seal, and beluga. Beyond compensating for elevated DEE, there was little benefit from terrestrial foraging toward prolonging the predicted time to starvation, as 19 of 20 bears lost mass (0.4-1.7 kg•day-1). Although polar bears on land exhibit remarkable behavioral plasticity, our findings reinforce the risk of starvation, particularly in subadults, with forecasted increases in the onshore period.

Adapting to ever-changing conditions.

Experiments involving periodic stimuli shed light on the interplay between hyper-osmotic stress and glucose starvation in yeast cells.

Exposure to Chinese famine in early life and height across 2 generations: a longitudinal study based on the China Health and Nutrition Survey.

BACKGROUND: Poor nutrition early in life is associated with short stature, which is associated with increased risk of cardiovascular disease and mortality in later life. Less evidence is available about the impact of early-life nutrition on height growth in the subsequent generation. OBJECTIVES: This study investigated the associations of famine exposure in utero and early childhood with height across 2 generations. METHODS: We used longitudinal data from the China Health and Nutrition Survey. We included 5401 participants (F1) born in 1955-1966 (calendar year around the Chinese famine in 1959-1961) and their 3930 biological offspring (F2). We classified F1 participants into subgroups by famine exposure status (unexposed/exposed) and timing (fetal-/childhood-exposed) according to their birth year and grouped F2 by their parents' exposure. Linear regression models were applied to examine the associations of famine exposure with adult height of F1 and F2. Linear mixed effect models with fractional polynomial functions were performed to estimate the difference in height between exposure groups of F2 during childhood. RESULTS: Participants (F1) exposed to famine in utero or in childhood were shorter than those unexposed by 0.41 cm (95% CI: 0.03, 0.80) and 1.12 cm (95% CI: 0.75, 1.48), respectively. Offspring (F2) of exposed fathers were also shorter than those of unexposed parents by 1.07 cm (95% CI: 0.28, 1.86) during childhood (<18 y) and by 1.25 cm (95% CI: 0.07, 2.43) in adulthood (≥18 y), and those with exposed parents had a reduced height during childhood by 1.29 cm (95% CI: 0.68, 1.89) (all P values < 0.05). The associations were more pronounced among child offspring of highly-educated F1, particularly for paternal exposure and among female offspring (all P for interaction < 0.05). CONCLUSIONS: The findings support the intergenerational associations of famine exposure in early life with height in Chinese populations, indicating the public health significance of improving the nutritional status of mothers and children in the long run.

Mating-induced increase of kynurenine in Drosophila ovary enhances starvation resistance of progeny.

The maternal nutritional environment can impact progeny development, stress tolerance, and longevity. Such phenotypic variation of offspring resulting from the maternal environment is often referred to as the 'maternal effect' and is observed across taxa, including in humans. While some mechanisms behind maternal effects have been revealed, such as histone modification, many studies rely on drastic genetic or nutritional manipulation in describing these mechanisms. Here we aimed to reveal how the maternal environment is regulated under physiological conditions to affect the progeny. Specifically, we detailed metabolic regulation in oocytes in response to mating using Drosophila melanogaster fruit flies. Using liquid chromatography-mass spectrometry, we found that upon mating, the ovary metabolites shifted, predominantly toward increasing amino acids and the tryptophan/kynurenine (Kyn) pathway. This mating-induced increase in ovary Kyn was driven by increased Kyn production in the fat body, a functional counterpart of the mammalian liver and white adipose tissue and the source of Kyn storage for the ovary after mating. Furthermore, we show that maternal Kyn repression decreased the starvation resistance of progeny and that administering exogenous Kyn to the maternal generation enhanced the starvation resistance of female progeny. Taken together, these findings point to a previously unidentified role of fat body Kyn distribution during reproduction on progeny survival.

Severe starvation and restraint in a 47-year-old woman: Clinical, autopsy and histopathological evidence of abuse and neglect.

The recognition of abuse and/or neglect still represents a challenge for both clinicians and forensic pathologists. Whereas abusive behaviors have been largely described among pediatric and elderly populations, adults' abuse and neglect is less frequently encountered, and therefore investigated. We report a case of a middle-aged woman without any known organic or psychiatric disorders who died of a multiple organ failure (MOF) due to extreme cachexia and bed-resting syndrome. The integration of all clinical, autopsy and histopathological data highlighted a picture of severe malnutrition, restraint, and widespread traumatic injuries related to abuse and neglect. We believe that the case here presented could be useful for both clinicians and forensic pathologists as it underlines once again the importance of collecting and integrating all medical evidence (both in the ante- and post-mortem settings) for reconstructing the most probable pathophysiology of disorders and injuries, comparing that reconstruction with the allegations of the caregivers, and thus identifying any potential abuse and/or neglect behaviors.

Metabolic stress-induced long ncRNA transcription governs the formation of meiotic DNA breaks in the fission yeast fbp1 gene.

Meiotic recombination is a pivotal process that ensures faithful chromosome segregation and contributes to the generation of genetic diversity in offspring, which is initiated by the formation of double-strand breaks (DSBs). The distribution of meiotic DSBs is not uniform and is clustered at hotspots, which can be affected by environmental conditions. Here, we show that non-coding RNA (ncRNA) transcription creates meiotic DSBs through local chromatin remodeling in the fission yeast fbp1 gene. The fbp1 gene is activated upon glucose starvation stress, in which a cascade of ncRNA-transcription in the fbp1 upstream region converts the chromatin configuration into an open structure, leading to the subsequent binding of transcription factors. We examined the distribution of meiotic DSBs around the fbp1 upstream region in the presence and absence of glucose and observed several new DSBs after chromatin conversion under glucose starvation conditions. Moreover, these DSBs disappeared when cis-elements required for ncRNA transcription were mutated. These results indicate that ncRNA transcription creates meiotic DSBs in response to stress conditions in the fbp1 upstream region. This study addressed part of a long-standing unresolved mechanism underlying meiotic recombination plasticity in response to environmental fluctuation.