In this translational review, we examine the evidence related to the impact of energy balance on triple negative breast cancer incidence and prognosis. We highlight the effect of interventions to alter energy balance on the efficacy of immune therapy as an understudied area deserving of more attention.
This paper presents a mutational approach to predict which tumors will respond to insulin-lowering metabolic therapy for breast cancer, and further shows for the first time that there may be benefit in adding insulin-lowering agents in lean animals in addition to obese.
In this manuscript we demonstrate differential metabolic dependency in lung adenocarcinoma vs. squamous cell carcinoma.
Leitner BP, Perry RJ (2020). The Impact of Obesity on Tumor Glucose Uptake in Breast and Lung Cancer. JNCI Cancer Spectrum 4(2): pkaa007.
Here we demonstrate that BMI correlates positively with tumor glucose uptake in breast cancer but negatively with tumor glucose uptake in non-small cell lung cancer using publicly available human PET-CT data.
This manuscript demonstrates that an SGLT2 inhibitor is effective in obese mouse models of breast and colon cancer due to its insulin-lowering effects.
Here we show that responsiveness to insulin – by increasing glucose uptake and oxidation in tumor cells in vitro is a hallmark of obesity-associated tumors.
This study, the first cancer paper from the Perry lab, shows that mitochondrial uncoupling with a controlled release mitochondrial protonophore (see Science 2015 paper below) slows colon cancer growth in two obese mouse models.
Here we use tracer-based metabolic flux analysis to explore the metabolic scaling phenotype (Klieber’s law), demonstrating that scaling scales across levels of organization and across tissues in vivo.
This study demonstrates that glucagon promotes both hepatic mitochondrial oxidation and gluconeogenesis through IP3R1-mediated calcium signaling and identifies short-term glucagon treatment as a therapy for NAFLD in rodents.
This paper demonstrates that hypercorticosteronemia (due to hypoleptinemia in diabetic ketoacidosis and in starvation, and independent of leptin during insulin-induced hypoglycemia) causes hyperphagia in an AgRP-dependent manner.
In this study we found that in a prolonged fast, hypoleptinemia activates the HPA axis, increasing lipolysis and hepatic acetyl-CoA content to maintain gluconeogenesis; however, as the fast progresses, substrate limitation due to reduced glucose-alanine cycling as a result of hypoglycemia limits hepatic gluconeogenic and oxidative capacity.
In a well-established rat model of type 2 diabetes, short-term very low calorie feeding improves glycemia by lowering hepatic acetyl-CoA and diacylglycerol concentrations.
In this paper, a follow-up to our 2014 Nat Med leptin study, we provide direct evidence that leptin reverses diabetic ketoacidosis by suppressing HPA axis activity.
This manuscript reports a non-invasive method – measurement of beta-hydroxybutyrate turnover – as a surrogate to measure hepatic acetyl-CoA, the primary allosteric activator of pyruvate carboxylase and thus of gluconeogenesis.
Here we show that gut microbiota-produced acetate activates the parasympathetic nervous system to promote insulin secretion in overfed rodents, generating a feed-forward loop that exacerbates obesity.
This paper reports a controlled-release mitochondrial protonophore capable of reversing NAFLD, NASH, and liver fibrosis in rodents. This finding has recently been translated to nonhuman primates: Goedeke et al. Sci. Transl. Med. 2019.
This paper demonstrates that acetyl-CoA is the main regulator of the impact of insulin to suppress hepatic gluconeogenesis (by suppressing white adipose tissue lipolysis) and the impact of inflammatory cytokines to promote gluconeogenesis in obesity by increasing lipolysis.
Here we show that hyperglycemia in diabetic ketoacidosis is caused, at least in part, by hypoleptinemia leading to increased HPA axis activity and unrestrained gluconeogenesis.
Perry Lab 