Roberta Haddad-Tóvolli

Hypothalamic POMC neurons modulate systemic energy balance and glucose homeostasis by sensing nutritional state signals. In addition to this classic regulatory mode, these neurons are also activated by the sensory perception of food. Here, we report that food-related sensory cues engage glycogen metabolism in POMC neurons. Genetic depletion of glycogen through various approaches renders POMC neurons unresponsive to food-associated sensory stimuli. This defective perception of food is linked to alterations in consummatory behaviour, hepatic adaptations and cephalic insulin release associated with a prediabetic phenotype that progresses into overweight and overt diabetes with a high-calorie diet or ageing. Collectively, our results posit glycogen as a decisive fuel resource for meeting the rapid and demanding energy requirements linked with sensory activation. Furthermore, our data delineate the biological function of food perception and provide support for the physiological relevance of neuronal glycogen.

The melanocortin system is fundamental for the regulation of whole-body energy homeostasis. This system consists of pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARH), as well as downstream neurons expressing melanocortin receptors (MCRs) located in various brain regions. Emerging evidence highlights significant anatomical and functional sex differences within the melanocortin system, influencing sex-dimorphic metabolic adaptations, the regulation of appetite and energy expenditure and susceptibility to metabolic conditions. These differences are primarily shaped by sex hormones, genetic and environmental factors as well as distinct neurocircuitry organization between males and females. These sex-specific regulatory mechanisms have important implications for the pathophysiology of metabolic disorders, including obesity, type 2 diabetes, and eating disorders. In this review, we explore current knowledge on sex differences in the development and function of the melanocortin system and how this is translated into sex-dimorphic control of metabolism. This emphasizes the need to incorporate sex as a critical variable in both metabolic research and clinical studies. Understanding these mechanisms may provide more precise and effective therapeutic strategies for metabolic disorders, obesity, and appetite dysregulation in both sexes.

In recent years, the gut microbiota and derived metabolites have emerged as relevant players in modulating several brain functions, including energy balance control^1,2,3. This form of distant communication mirrors that of metabolic hormones (for example, leptin, ghrelin), which convey information about the organism’s energy status by exerting effects on diverse brain regions, including the master homeostatic centre, the hypothalamus⁴. However, whether the hypothalamus is also able to influence gut microbiota composition remains enigmatic. Here we present a study designed to unravel this challenging question. To this aim, we used chemogenetics⁵ (to selectively activate or inhibit hypothalamic pro-opiomelanocortin or agouti-related peptide neurons) or centrally administered leptin or ghrelin to male mice. Subsequently, we conducted microbiota composition analysis throughout the gut using 16S rRNA gene sequencing. Our results showed that these brain interventions significantly changed the gut microbiota in an anatomical and short-term (2–4 h) fashion. Transcriptomic analysis indicated that these changes were associated with the reconfiguration of neuronal and synaptic pathways in the duodenum concomitant with increased sympathetic tone. Interestingly, diet-induced obesity attenuated the brain-mediated changes triggered by leptin in gut microbiota communities and sympathetic activation. Our findings reveal a previously unanticipated brain–gut axis that acutely attunes microbiota composition on fast timescales, with potential implications for meal-to-meal adjustments and systemic energy balance control.

The consumption of large amounts of dietary fats and pregnancy are independent factors that can promote changes in gut permeability and the gut microbiome landscape. However, there is limited evidence regarding the impact of pregnancy on the regulation of such parameters in females fed a high-fat diet. Here, gut permeability and microbiome landscape were evaluated in a mouse model of diet-induced obesity in pregnancy. The results show that pregnancy protected against the harmful effects of the consumption of a high-fat diet as a disruptor of gut permeability; thus, there was a two-fold reduction in FITC–dextran passage to the bloodstream compared to non-pregnant mice fed a high-fat diet (p < 0.01). This was accompanied by an increased expression of gut barrier-related transcripts, particularly in the ileum. In addition, the beneficial effect of pregnancy on female mice fed the high-fat diet was accompanied by a reduced presence of bacteria belonging to the genus Clostridia, and by increased Lactobacillus murinus in the gut (p < 0.05). Thus, this study advances the understanding of how pregnancy can act during a short window of time, protecting against the harmful effects of the consumption of a high-fat diet by promoting an increased expression of transcripts encoding proteins involved in the regulation of gut permeability, particularly in the ileum, and promoting changes in the gut microbiome.

Modern lifestyle is associated with a major consumption of ultra–processed foods (UPF) due to their practicality and palatability. The ingestion of emulsifiers, a main additive in UPFs, has been related to gut inflammation, microbiota dysbiosis, adiposity, and obesity. Maternal unbalanced nutritional habits during embryonic and perinatal stages perturb offspring’s long–term metabolic health, thus increasing obesity and associated comorbidity risk. However, whether maternal emulsifier consumption influences developmental programming in the offspring remains unknown. Here, we show that, in mice, maternal consumption of dietary emulsifiers (1% carboxymethyl cellulose (CMC) and 1% P80 in drinking water), during gestation and lactation, perturbs the development of hypothalamic energy balance regulation centers of the progeny, leads to metabolic impairments, cognition deficits, and induces anxiety–like traits in a sex–specific manner. Our findings support the notion that maternal consumption of emulsifiers, common additives of UPFs, causes mild metabolic and neuropsychological malprogramming in the progeny. Our data call for nutritional advice during gestation.

Eating behaviours are determined by the integration of interoceptive and environmental inputs. During pregnancy, numerous physiological adaptations take place in the maternal organism to provide an adequate environment for embryonic growth. Among them, whole-body physiological remodelling directly influences eating patterns, commonly causing notable taste perception alterations, food aversions and cravings. Recurrent food cravings for and compulsive eating of highly palatable food can contribute to the development and maintenance of gestational overweight and obesity with potential adverse health consequences for the offspring. Although much is known about how maternal eating habits influence offspring health, the mechanisms that underlie changes in taste perception and food preference during pregnancy (which guide and promote feeding) are only just starting to be elucidated. Given the limited and diffuse understanding of the neurobiology of gestational eating patterns, the aim of this Review is to compile, integrate and discuss the research conducted on this topic in both experimental models and humans. This article sheds light on the mechanisms that drive changes in female feeding behaviours during distinct physiological states. Understanding these processes is crucial to improve gestational parent health and decrease the burden of metabolic and food-related diseases in future generations.

The internal state of an animal, including homeostatic requirements, modulates its behavior. Negative energy balance stimulates hunger, thus promoting a range of actions aimed at obtaining food. While these survival actions are well established, the influence of the energy status on prosocial behavior remains unexplored. We developed a paradigm to assess helping behavior in which a free mouse was faced with a conspecific trapped in a restrainer. We measured the willingness of the free mouse to liberate the confined mouse under diverse metabolic conditions. Around 42% of ad libitum–fed mice exhibited a helping behavior, as evidenced by the reduction in the latencies to release the trapped cagemate. This behavior was independent of subsequent social contact reward and was associated with changes in corticosterone indicative of emotional contagion. This decision-making process was coupled with reduced blood glucose excursions and higher Adenosine triphosphate (ATP):Adenosine diphosphate (ADP) ratios in the forebrain of helper mice, suggesting that it was a highly energy-demanding process. Interestingly, chronic (food restriction and type 2 diabetes) and acute (chemogenetic activation of hunger-promoting AgRP neurons) situations mimicking organismal negative energy balance and enhanced appetite attenuated helping behavior toward a distressed conspecific. To investigate similar effects in humans, we estimated the influence of glycated hemoglobin (a surrogate of long-term glycemic control) on prosocial behavior (namely charity donation) using the Understanding Society dataset. Our results evidenced that organismal energy status markedly influences helping behavior and that hypothalamic AgRP neurons are at the interface of metabolism and prosocial behavior.

Maternal dietary habits directly influence offspring health. In this study, we aimed at determining the impact of maternal obesity on BBB integrity. We show that DIO offspring presented a leakier ME–BBB, accompanied by changes in the expression of transcripts encoding for endothelial and tanycytic proteins, as well as of hypothalamic neuropeptides. Breastfeeding in lean dams was sufficient to protect the offspring from ME–BBB disruption, providing a preventive strategy of nutritional intervention during early life.