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Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. Here, we establish that aging of the immune system, regardless of the age of the stroma and tumor, drives lung cancer progression. Hematopoietic aging enhances emergency myelopoiesis, resulting in the local accumulation of myeloid progenitor-like cells in lung tumors. These cells are a major source of IL-1⍺ that drives the enhanced myeloid response. The age-associated decline of DNMT3A enhances IL-1⍺ production, and disrupting IL-1R1 signaling early during tumor development normalized myelopoiesis and slowed the growth of lung, colonic, and pancreatic tumors. In human tumors, we identified an enrichment for IL-1⍺-expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies.

Exercise, stress, sleep and diet are four distinct but intertwined lifestyle factors that influence the cardiovascular system. Abundant epidemiological, clinical and preclinical studies have underscored the importance of managing stress, having good sleep hygiene and responsible eating habits and exercising regularly. We are born with a genetic blueprint that can protect us against or predispose us to a particular disease. However, lifestyle factors build upon and profoundly influence those predispositions. Studies in the past 10 years have shown that the immune system in general and leukocytes in particular are particularly susceptible to environmental perturbations. Lifestyle factors such as stress, sleep, diet and exercise affect leukocyte behaviour and function and thus the immune system at large. In this Review, we explore the various mechanisms by which lifestyle factors modulate haematopoiesis and leukocyte migration and function in the context of cardiovascular health. We pay particular attention to the role of the nervous system as the key executor that connects environmental influences to leukocyte behaviour., (© 2023. Springer Nature Limited.)

Nutrition can influence the brain and affect its regulation of food intake, especially that of high-palatable foods. We hypothesize that fat and sugar have interacting effects on the brain, and the lateral hypothalamus (LH) is a prime candidate to be involved in this interaction. The LH is a heterogeneous area, crucial for regulating consummatory behaviors, and integrating homeostatic and hedonic needs. GABAergic LH neurons stimulate feeding when activated, and are responsive to consummatory behavior while encoding sucrose palatability. Previously, we have shown that glutamatergic LH neurons reduce their activity in response to sugar drinking and that this response is disturbed by a free-choice high-fat diet (fcHFD). Whether GABAergic LH neurons, and their response to sugar, is affected by a fcHFD is yet unknown. Using head-fixed two-photon microscopy, we analyzed activity changes in LH Vgat neuronal activity in chow or fcHFD-fed mice in response to water or sucrose drinking. A fcHFD decreased overall LH Vgat neuronal activity, without disrupting the sucrose-induced increase. When focusing on the response per unique neuron, a vast majority of neurons respond inconsistently over time. Thus, a fcHFD dampens overall LH GABAergic activity, while it does not disturb the response to sucrose. The inconsistent responding over time suggests that it is not one specific subpopulation of LH GABAergic neurons that is driving these behaviors, but rather a result of the integrative properties of a complex neural network. Further research should focus on determining how this dampening of LH GABAergic activity contributes to hyperphagia and the development of obesity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Slomp, Koekkoek, Mutersbaugh, Linville, Luquet and la Fleur.)

Diet profoundly influences physiology. Whereas over-nutrition elevates risk for disease via its influence on immunity and metabolism, caloric restriction and fasting appear to be salutogenic. Despite multiple correlations observed between diet and health, the underlying biology remains unclear. Here, we identified a fasting-induced switch in leukocyte migration that prolongs monocyte lifespan and alters susceptibility to disease in mice. We show that fasting during the active phase induced the rapid return of monocytes from the blood to the bone marrow. Monocyte re-entry was orchestrated by hypothalamic-pituitary-adrenal (HPA) axis-dependent release of corticosterone, which augmented the CXCR4 chemokine receptor. Although the marrow is a safe haven for monocytes during nutrient scarcity, re-feeding prompted mobilization culminating in monocytosis of chronologically older and transcriptionally distinct monocytes. These shifts altered response to infection. Our study shows that diet-in particular, a diet's temporal dynamic balance-modulates monocyte lifespan with consequences for adaptation to external stressors., Competing Interests: Declaration of interests M.N. has received funding or material research support from Alnylam, Biotronik, CSL Behring, GlycoMimetics, GSK, Medtronic, Novartis, and Pfizer as well as consulting fees from Lilly, Biogen, Gimv, IFM Therapeutics, Molecular Imaging, Sigilon, and Verseau Therapeutics. F.K.S. has received funds or material research support from Novartis, Partner Therapeutics, Pfizer, and Verseau Therapeutics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives : We have previously shown that the combined consumption of fat and a sucrose solution induces overeating, and there is evidence indicating that sucrose drinking directly stimulates fat intake. One neurochemical pathway by which sucrose may enhance fat intake is through the release of endogenous opioids in the nucleus accumbens (NAC). Methods : To test this hypothesis, we provided rats with a free-choice high-fat diet for two weeks. During the second week, rats had access to an additional bottle of water or a 30% sucrose solution for five minutes per day. After these two weeks, we infused vehicle or the μ-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) into the NAC 30 min after their daily access to the additional bottle of water or the sucrose solution. Results : Sucrose drinking had two effects, (1) it stimulated fat intake in the absence of DAMGO infusion, (2) it diminished sensitivity to DAMGO, as it prevented the rapid increase in fat intake typically seen upon DAMGO infusion in the nucleus accumbens. In a second experiment, we confirmed that these results are not due to the ingested calories of the sucrose solution. Lastly, we investigated which brain areas are involved in the observed effects on fat intake by assessing c-Fos-expression in brain areas previously linked to DAMGO's effects on food intake. Both intra-NAC DAMGO infusion and sucrose consumption in the absence of DAMGO infusion had no effect on c-Fos-expression in orexin neurons and the central amygdala but increased c-Fos-expression in the NAC as well as the basolateral amygdala. Discussion : In conclusion, we confirm that sucrose drinking stimulates fat intake, likely through the release of endogenous opioids.

Purpose of Review: We are currently in the midst of a global opioid epidemic. Opioids affect many physiological processes, but one side effect that is not often taken into consideration is the opioid-induced alteration in blood glucose levels., Recent Findings: This review shows that the vast majority of studies report that opioid stimulation increases blood glucose levels. In addition, plasma levels of the endogenous opioid β-endorphin rise in response to low blood glucose. In contrast, in hyperglycaemic baseline conditions such as in patients with type 2 diabetes mellitus (T2DM), opioid stimulation lowers blood glucose levels. Furthermore, obesity itself alters sensitivity to opioids, changes opioid receptor expression and increases plasma β-endorphin levels. Thus, opioid stimulation can have various side effects on glycaemia that should be taken into consideration upon prescribing opioid-based medication, and more research is needed to unravel the interaction between obesity, glycaemia and opioid use., (© 2022. The Author(s).)

Central dopamine signaling regulates reward-related aspects of feeding behavior, and during diet-induced obesity dopamine receptor signaling is altered. Yet, the influence of dopamine signaling on the consumption of specific dietary components remains to be elucidated. We have previously shown that 6-hydroxydopamine-mediated lesions of dopamine neuron terminals in the lateral shell of the nucleus accumbens promotes fat intake in rats fed a multi-component free-choice high-fat high-sugar (fcHFHS) diet. It is however not yet determined which dopamine receptors are responsible for this shift towards fat preference. In this study, we assess the effects of D1-or D2 receptor acute inhibition in the lateral shell of the nucleus accumbens on fcHFHS diet consumption. We report that infusion of the D1 receptor antagonist SCH2 3390, but not the D2 receptor antagonist raclopride, promotes dietary fat consumption in male Sprague Dawley rats on a fcHFHS diet during 2 h after infusion. Furthermore, anatomical analysis of infusion sites revealed that the rostral region, but not the caudal region, of the lateral shell of the nucleus accumbens is sensitive to the D1 receptor inhibition effects on fat consumption. Our data highlight a role for D1 receptors in the rostral region of the lateral shell of the nucleus accumbens to control dietary fat consumption., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

During the last few decades, the consumption of low-calorie sweeteners, as a substitute for caloric sweeteners, has sharply increased. Although research shows that caloric versus low-calorie sweeteners can have differential effects on the brain, it is unknown which neuronal populations are responsible for detecting the difference between the two types of sweeteners. Using in vivo two-photon calcium imaging, we investigated how drinking sucrose or sucralose (a low-calorie sweetener) affects the activity of glutamatergic neurons in the lateral hypothalamus. Furthermore, we explored the consequences of consuming a free-choice high fat diet on the calorie detection abilities of these glutamatergic neurons. We found that glutamatergic neurons indeed can discriminate sucrose from water and sucralose, and that consumption of a free-choice high fat diet shifts the glutamatergic neuronal response from sucrose-specific to sucralose-specific, thereby disrupting calorie detection. These results highlight the disruptive effects of a diet high in saturated fat on calorie detection in the lateral hypothalamus., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Opioids are known to affect blood glucose levels but their exact role in the physiological control of glucose metabolism remains unclear. Although there are numerous studies investigating the peripheral effects of opioid stimulation, little is known about how central opioids control blood glucose and which brain areas are involved. One brain area possibly involved is the nucleus accumbens because, as well as being a key site for opioid effects on food intake, it has also been implicated in the control of blood glucose levels. Within the nucleus accumbens, μ-opioid receptors are most abundantly expressed. Therefore, in the present study, we investigated the role of μ-opioid receptors in the nucleus accumbens in the control of glucose metabolism. We show that infusion of the μ-opioid receptor agonist [d-Ala 2 , N-MePhe 4 , Gly-ol]-enkephalin (DAMGO) in the nucleus accumbens by itself does not affect blood glucose levels, but it enhances the glycaemic response after both an insulin tolerance test, as well as a glucose tolerance test. These findings indicate that the nucleus accumbens plays a role in the central effects of opioids on glucose metabolism, and highlight the possibility of nucleus accumbens μ-opioid receptors as a therapeutic target for enhancing the counter-regulatory response., (© 2021 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Interaction between the gut and the brain is essential for energy homeostasis. In obesity, this homeostasis is disrupted, leading to a positive energy balance and weight gain. Obesity is a global epidemic that affects individual health and strains the socioeconomic system. Microbial dysbiosis has long been reported in obesity and obesity-related disorders. More recent literature has focused on the interaction of the gut microbiota and its metabolites on human brain and behavior. Developing strategies that target the gut microbiota could be a future approach for the treatment of obesity. Here, we review the microbiota-gut-brain axis and possible therapeutic options.

The consumption of saturated fat and sucrose can have synergistic effects on the brain that do not occur when either nutrient is consumed by itself. In this study we hypothesize that saturated fat intake modulates glucose handling in the hypothalamus and nucleus accumbens, both brain areas highly involved in the control of food intake. To study this, male Wistar rats were given a free-choice high fat diet (fcHFD) or a control diet for two weeks. During the last seven days rats were given a daily bolus of either a 30% sucrose solution or water. Rats were sacrificed on day eight, 30 minutes after the onset of drinking. mRNA and protein levels of genes involved in glucose handling were assessed in the hypothalamus and nucleus accumbens. We found increased Glut3 and Glut4 mRNA in the hypothalamus of fcHFD-fed rats without an additional effect of the sucrose bolus. In the nucleus accumbens, the sucrose bolus increased Glut3 mRNA and decreased Glut4 mRNA independent of prior diet exposure. The ATP-sensitive potassium channel subunit Kir6.1 in the nucleus accumbens tended to be affected by the synergistic effects of a fcHFD and a sucrose bolus. These data suggest that acute glucose handling in the hypothalamus and nucleus accumbens may be affected by prior high fat exposure., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Eating out of phase with the endogenous biological clock alters clock and metabolic gene expression in rodents and can induce obesity and type 2 diabetes mellitus. Diet composition can also affect clock gene expression. This study assessed the combined effect of diet composition and feeding time on (1) body composition, (2) energy balance, and (3) circadian expression of hepatic clock and metabolic genes., Methods: Male Wistar rats were fed a chow or a free-choice high-fat, high-sugar (fcHFHS) diet, either ad libitum or with food access restricted to either the light or dark period. Body weight, adiposity, and hepatic fat accumulation as well as hepatic clock and metabolic mRNA expression were measured after 5 weeks of the diet. Energy expenditure was measured using calorimetric cages., Results: Animals with access to the fcHFHS diet only during the light period showed more hepatic fat accumulation than fcHFHS dark-fed animals despite less calories consumed. In contrast, within the chow-fed groups, light-fed animals showed the lowest hepatic fat content, but they also showed the lowest caloric intake. Locomotor activity and heat production followed feeding times, except in the fcHFHS light-fed group. Hepatic clock and metabolic gene expression rhythms also followed timing of food intake. Yet, in the fcHFHS light-fed animals, clock gene expression appeared 3 hours advanced compared with chow light-fed animals, an effect not observed in the fcHFHS dark-fed animals., Conclusions: An fcHFHS diet consumed in the light period promotes hepatic fat accumulation and advances clock gene expression in male Wistar rats, likely because of a mismatch between energy intake and expenditure., (© 2020 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society (TOS).)

Humans have engineered a dietary environment that has driven the global prevalence of obesity and several other chronic metabolic diseases to pandemic levels. To prevent or treat obesity and associated comorbidities, it is crucial that we understand how our dietary environment, especially in combination with a sedentary lifestyle and/or daily-life stress, can dysregulate energy balance and promote the development of an obese state. Substantial mechanistic insight into the maladaptive adaptations underlying caloric overconsumption and excessive weight gain has been gained by analysing brains from rodents that were eating prefabricated nutritionally-complete pellets of high-fat diet (HFD). Although long-term consumption of HFDs induces chronic metabolic diseases, including obesity, they do not model several important characteristics of the modern-day human diet. For example, prefabricated HFDs ignore the (effects of) caloric consumption from a fluid source, do not appear to model the complex interplay in humans between stress and preference for palatable foods, and, importantly, lack any aspect of choice. Therefore, our laboratory uses an obesogenic free-choice high-fat high-sucrose (fc-HFHS) diet paradigm that provides rodents with the opportunity to choose from several diet components, varying in palatability, fluidity, texture, form and nutritive content. Here, we review recent advances in our understanding how the fc-HFHS diet disrupts peripheral metabolic processes and produces adaptations in brain circuitries that govern homeostatic and hedonic components of energy balance. Current insight suggests that the fc-HFHS diet has good construct and face validity to model human diet-induced chronic metabolic diseases, including obesity, because it combines the effects of food palatability and energy density with the stimulating effects of variety and choice. We also highlight how behavioural, physiological and molecular adaptations might differ from those induced by prefabricated HFDs that lack an element of choice. Finally, the advantages and disadvantages of using the fc-HFHS diet for preclinical studies are discussed., (© 2019 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Glucose-sensing neurons are neurons that alter their activity in response to changes in extracellular glucose. These neurons, which are an important mechanism the brain uses to monitor changes in glycaemia, are present in the hypothalamus, where they have been thoroughly investigated. Recently, glucose-sensing neurons have also been identified in brain nuclei which are part of the reward system. However, little is known about the molecular mechanisms by which they function, and their role in the reward system. We therefore aim to provide an overview of molecular mechanisms that have been studied in the hypothalamic glucose-sensing neurons, and investigate which of these transporters, enzymes and channels are present in the reward system. Furthermore, we speculate about the role of glucose-sensing neurons in the reward system.