Immunometabolism within the tumor microenvironment is an appealing target for precision therapy approaches in lung cancer. Interestingly, obesity confers an improved response to immune checkpoint inhibition in non-small cell lung cancer (NSCLC), suggesting intriguing relationships between systemic metabolism and the immunometabolic environment in lung tumors. We hypothesized that visceral fat and 18F-Fluorodeoxyglucose uptake influenced the tumor immunometabolic environment and that these bidirectional relationships differ in NSCLC subtypes, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). By integrating 18F-FDG PET/CT imaging, bulk and single-cell RNA-sequencing, and histology, we observed that LUSC had a greater dependence on glucose than LUAD. In LUAD tumors with high glucose uptake, glutaminase was downregulated, suggesting a tradeoff between glucose and glutamine metabolism, while in LUSC tumors with high glucose uptake, genes related to fatty acid and amino acid metabolism were also increased. We found that tumor-infiltrating T cells had the highest expression of glutaminase, ribosomal protein 37, and cystathionine gamma-lyase in NSCLC, highlighting the metabolic flexibility of this cell type. Further, we demonstrate that visceral adiposity, but not body mass index (BMI), was positively associated with tumor glucose uptake in LUAD and that patients with high BMI had favorable prognostic transcriptional profiles, while tumors of patients with high visceral fat had poor prognostic gene expression. We posit that metabolic adjunct therapy may be more successful in LUSC rather than LUAD due to LUAD's metabolic flexibility and that visceral adiposity, not BMI alone, should be considered when developing precision medicine approaches for the treatment of NSCLC. © 2022. The Author(s).

Obesity and type 2 diabetes (T2D) increase the prevalence and worsen the prognosis of more than a dozen tumor types; however, the mechanism for this association remains hotly debated. Here we discuss a potential role for insulin as the key hormonal mediator of tumor metabolism and growth in obesity-associated insulin resistance.

Nonalcoholic fatty liver disease (NAFLD) is estimated to affect up to one-third of the general population, and new therapies are urgently required. Our laboratory previously developed a controlled-release mitochondrial protonophore (CRMP) that is functionally liver-targeted and promotes oxidation of hepatic triglycerides. Although we previously demonstrated that CRMP safely reverses hypertriglyceridemia, fatty liver, hepatic inflammation, and fibrosis in diet-induced rodent models of obesity, there remains a critical need to assess its safety and efficacy in a model highly relevant to humans. Here, we evaluated the impact of longer-term CRMP treatment on hepatic mitochondrial oxidation and on the reversal of hypertriglyceridemia, NAFLD, and insulin resistance in high-fat, fructose-fed cynomolgus macaques (n = 6) and spontaneously obese dysmetabolic rhesus macaques (n = 12). Using positional isotopomer nuclear magnetic resonance tracer analysis (PINTA), we demonstrated that acute CRMP treatment (single dose, 5 mg/kg) increased rates of hepatic mitochondrial fat oxidation by 40%. Six weeks of CRMP treatment reduced hepatic triglycerides in both nonhuman primatemodels independently of changes in body weight, food intake, body temperature, or adverse reactions. CRMP treatment was also associatedwith a 20 to 30% reduction in fasting plasma triglycerides and low-density lipoprotein (LDL)-cholesterol in dysmetabolic nonhuman primates. Oral administration of CRMP reduced endogenous glucose production by 18%, attributable to a 20% reduction in hepatic acetyl-coenzyme A (CoA) content [as assessed by whole-body beta-hydroxybutyrate (beta-OHB) turnover] and pyruvate carboxylase flux. Collectively, these studies provide proof-of-concept data to support the development of liver-targeted mitochondrial uncouplers for the treatment of metabolic syndrome in humans.

Leptin informs the brain about sufficiency of fuel stores. When insufficient, leptin levels fall, triggering compensatory increases in appetite. Falling leptin is first sensed by hypothalamic neurons, which then initiate adaptive responses. With regard to hunger, it is thought that leptin-sensing neurons work entirely via circuits within the central nervous system (CNS). Very unexpectedly, however, we now show this is not the case. Instead, stimulation of hunger requires an intervening endocrine step, namely activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Increased corticosterone then activates AgRP neurons to fully increase hunger. Importantly, this is true for 2 forms of low leptin-induced hunger, fasting and poorly controlled type 1 diabetes. Hypoglycemia, which also stimulates hunger by activating CNS neurons, albeit independently of leptin, similarly recruits and requires this pathway by which HPA axis activity stimulates AgRP neurons. Thus, HPA axis regulation of AgRP neurons is a previously underappreciated step in homeostatic regulation of hunger.