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Loss of appetite and negative energy balance are common features of endotoxemia in all animals and are thought to have protective roles by reducing nutrient availability to host and pathogen metabolism. Accordingly, fasting and caloric restriction have well-established anti-inflammatory properties. However, in response to reduced nutrient availability at the cellular and organ levels, negative energy balance also recruits distinct energy-sensing brain circuits, but it is not known whether these neuronal systems have a role in its anti-inflammatory effects. Here, we report that hypothalamic AgRP neurons-a critical neuronal population for the central representation of negative energy balance-have parallel immunoregulatory functions. We found that when endotoxemia occurs in fasted mice, the activity of AgRP neurons remains sustained, but this activity does not influence feeding behavior and endotoxemic anorexia. Furthermore, we found that endotoxemia acutely desensitizes AgRP neurons, which also become refractory to inhibitory signals. Mimicking this sustained AgRP neuron activity in fed mice by chemogenetic activation-a manipulation known to recapitulate core behavioral features of fasting-results in reduced acute tumor necrosis factor alpha (TNF-α) release during endotoxemia. Mechanistically, we found that endogenous glucocorticoids play an important role: glucocorticoid receptor deletion from AgRP neurons prevents their endotoxemia-induced desensitization, and importantly, it counteracts the fasting-induced suppression of TNF-α release, resulting in prolonged sickness. Together, these findings provide evidence directly linking AgRP neuron activity to the acute response during endotoxemia, suggesting that these neurons are a functional component of the immunoregulatory effects associated with negative energy balance and catabolic metabolism.

Repeated episodes throughout history remind us that AFSs episodically undergo dramatic transformations, most of them purposeful—guided by incentives prevailing at the time—rather than purely random changes. Typically, these changes have taken decades or centuries. A major shock, like the COVID-19 pandemic, may help spark the more rapid transformation that we desperately need. Hence the value of explicitly envisioning AFS transformation to direct the transformative power unleashed by the pandemic towards desired outcomes.

As we look 25–50 years, or more, into the future, we must also keep in mind how very different tomorrow’s world will inevitably look. Three big, inevitable changes stand out, with serious implications for AFS and AVC innovations.

Sustainable Development Goals Series, ISSN:2523-3084, ISSN:2523-3092, ISBN:978-3-030-88801-5, ISBN:978-3-030-88804-6, ISBN:978-3-030-88802-2

A key implication of the abundance of promising technologies in various stages of development is that AFS transformation is less likely to be limited by science-based discovery than by human agency. What key players do in response to the wealth of options they face will ultimately determine the path(s) we follow.

So how do we reverse the growing carbon, land, and toxic chemical footprint of contemporary AVCs; expand the nutrient-rich food supply; and induce more equitable, inclusive, healthier food environments—and thus consumption patterns—so as to navigate from today’s unsustainable and precarious AVCs to a warmer, more urban, more African, and shock-prone world in which wealthier consumers place an ever-growing premium on the non-nutritive attributes of the foods they buy? Given the climate change, population and income growth, and urbanization baked into AFSs already, beneficial innovation is the only feasible pathway. And because innovation takes time, typically measurable in decades, we urgently need to accelerate innovative activity.

The complex pathways from innovation to impact mean that unintended spillover effects on non-target objectives are always likely. This generates a third reason—in addition to accelerators and complementarity in pursuit of target objectives—why socio-technical bundles are important. Herrero et al. (2020, 2021) demonstrated that food systems innovations can have mostly neutral or positive effects on the food systems SDGs (left-hand panel of Fig. 1).

One might reasonably invoke Dickens in describing AFSs and AVCs today: “it was the best of times, it was the worst of times.”

Because AFSs are diverse, dynamic, and evolve continuously, they require massive continuous investment to enable ongoing discovery and adaptation merely to prevent backsliding.

As detailed in Marshall et al. (Quinn Marshall, Jessica Fanzo, Christopher B. Barrett, Andrew D. Jones, Anna Herforth, and Rebecca McLaren, “Building a global food systems typology: A new tool for reducing complexity in food systems analysis,” Frontiers in Sustainable Food Systems, vol. 5 (November 2021): 746512), the food systemstypologies we and the Food Systems Dashboard use were developed using a method that began with a structured scoping review of the existing food systems literature.

Scientific discovery is neither linear nor predictable. The time it takes to develop breakthrough technologies varies enormously among application domains. Some basic scientific discoveries remain elusive and will need continued, concerted funding and attention in the years and decades ahead. In some cases, the stumbling block is the scientific advancement per se, when important discoveries along the path towards technological readiness have not yet been made.

Objective Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications to reduce appetite and body weight. These actions are centrally mediated; however, the neuronal substrates involved are poorly understood. Methods We employed a combination of neuroanatomical, genetic, and behavioral approaches in the mouse to investigate the involvement of caudal brainstem cholecystokinin-expressing neurons in the effect of the GLP-1RA exendin-4. We further confirmed key neuroanatomical findings in the non-human primate brain. Results We found that cholecystokinin-expressing neurons in the caudal brainstem are required for the anorectic and body weight-lowering effects of GLP-1RAs and for the induction of GLP-1RA-induced conditioned taste avoidance. We further show that, while cholecystokinin-expressing neurons are not a direct target for glucose-dependent insulinotropic peptide (GIP), GIP receptor activation results in a reduced recruitment of these GLP-1RA-responsive neurons and a selective reduction of conditioned taste avoidance. Conclusions In addition to disclosing a neuronal population required for the full appetite- and body weight-lowering effect of GLP-1RAs, our data also provide a novel framework for understanding and ameliorating GLP-1RA-induced nausea — a major factor for withdrawal from treatment., Highlights • CCKAP/NTS neurons are required for the full anorectic and body weight-lowering effect of GLP-1 receptor agonists. • GLP-1 receptor agonists promote the formation of conditioned taste avoidance by activating CCKAP/NTS neurons. • CCKAP/NTS neurons are not activated in response to GIP receptor agonists. • GIP receptor agonists reduce GLP-1 receptor agonist-induced neuronal responses in the caudal brainstem. • GIP receptor agonists reduce GLP-1 receptor agonist-induced conditioned taste avoidance.