Regulation and evolution of extreme metabolic… (R35GM156744) – Project Grant to University Of Rochester

Abstract: Essentially all multicellular animals exhibit some form of metabolic plasticity in response to environmental or internal cues. This project seeks to increase our understanding of how metabolic and stress response pathways interact and are regulated and at both the cellular and organismal levels, as well as the mechanistic basis for the limits to this plasticity. The focus of this work is on an innovative system, ants, which feature extreme disparity in metabolism between phenotypic classes of individuals ("castes") within the same nest. Importantly, these differences are not genetic, but instead the product of environmentally-determined plasticity. The species focused on in this work (harpegnathos saltator) is particularly well-suited for understanding plasticity of stress resistance and metabolism: any individual can be induced to change caste - from non-reproductive to reproductive - in the lab on the order of days, a change that is fully reversible on the same time scale. I show evidence that changing caste results in a rapid, striking shift in global metabolism, consistent across multiple tissues, under the control of behavioral/social stimuli. Importantly, these shifts, which can be recapitulated in vitro, show strong evidence of engaging both metabolic and stress-response pathways typically seen as mutually exclusive, likely due to eusocial evolution uniquely prioritizing very high anabolism as well as long-lifespan in reproductive individuals. Further, comparative analyses reveal strikingly-similar signatures of gene expression between castes of one of the only eusocial mammals, suggesting evolution of eusociality may converge on regulation of these hugely-important pathways in multiple independent taxa. The proposed work will utilize in vivo and in vitro experiments in ants, d. Melanogaster, and the naked mole-RAT to understand how the unfolded protein response (UPR) and MYC-hyperactivity paradoxically appear to both be acting in a novel way to accomplish the metabolic differences between castes, how these differences are regulated organism-wide, and if the same regulation has evolved in a eusocial mammal. We will utilize custom antibodies and perturbations in vitro and in vivo to identify core components and unique upstream effectors, neuronal cultures that transcriptionally recapitulate castes to understand the hormonal regulation of this plasticity, and work with the naked mole RAT to understand how these signatures appear to have also evolved in a eusocial mammal. This work will not only shed light on the regulation and evolution of metabolic plasticity at both the cellular and organismal levels, but also how ants uniquely engage multiple conserved, medically-relevant metabolic regulators to uniquely accomplish a high-metabolism stress-protected state not seen in other systems.

Action	Obligated	Date
Amendment	$382,689	May 28, 2026
Original award	$367,808	May 28, 2025

Regulation and evolution of extreme metabolic plasticity in eusocial animals

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