Morris F. White

MASLD (metabolic-associated steatotic liver disease) and MASH (steatohepatitis) are closely associated with hepatic IR (insulin resistance) and T2D. Regardless, insulin-stimulated hepatic lipogenesis is considered essential for MASLD development, as mouse models of complete hepatic IR become diabetic without MASLD when fed high-fat diets. Challenging this notion, we found that male LDKO mice lacking hepatic insulin receptor substrates acutely developed MASLD if fed a fructose-enriched “MASH diet” (GAN) or high-fructose diet. Fructose potentiated hepatic re-esterification of abundant circulating fatty acids in LDKO mice, evidenced by excess ¹³C incorporation into the glycerol backbone—but not fatty acid chains—of hepatic triacylglyceride after gavage with [U¹³C]fructose. Suppressing adipose lipolysis in LDKO mice by inactivating hepatic Fst (Follistatin) prevented acute MASLD, whereas over-expressing Fst in wild-type mouse liver accelerated GAN-promoted MASLD/MASH. Compatibly, higher serum FST levels among Tübingen Diabetes Family Study participants clustered with increased adipose IR and greater hepatic triacylglyceride accumulation.

Major mental illnesses such as schizophrenia (SZ) and bipolar disorder (BP) frequently accompany metabolic conditions, but their relationship is still unclear, in particular at the mechanistic level. We implemented an approach of “from population to neuron”, combining population-based epidemiological analysis with neurobiological experiments using cell and animal models based on a hypothesis built from the epidemiological study. We characterized high-quality population data, olfactory neuronal cells biopsied from patients with SZ or BP, and healthy subjects, as well as mice genetically modified for insulin signaling. We accessed the Danish Registry and observed (1) a higher incidence of diabetes in people with SZ or BP and (2) higher incidence of major mental illnesses in people with diabetes in the same large cohort. These epidemiological data suggest the existence of common pathophysiological mediators in both diabetes and major mental illnesses. We hypothesized that molecules associated with insulin resistance might be such common mediators, and then validated the hypothesis by using two independent sets of olfactory neuronal cells biopsied from patients and healthy controls. In the first set, we confirmed an enrichment of insulin signaling-associated molecules among the genes that were significantly different between SZ patients and controls in unbiased expression profiling data. In the second set, olfactory neuronal cells from SZ and BP patients who were not pre-diabetic or diabetic showed reduced IRS2 tyrosine phosphorylation upon insulin stimulation, indicative of insulin resistance. These cells also displayed an upregulation of IRS1 protein phosphorylation at serine-312 at baseline (without insulin stimulation), further supporting the concept of insulin resistance in olfactory neuronal cells from SZ patients. Finally, Irs2 knockout mice showed an aberrant response to amphetamine, which is also observed in some patients with major mental illnesses. The bi-directional relationships between major mental illnesses and diabetes suggest that there may be common pathophysiological mediators associated with insulin resistance underlying these mental and physical conditions.

The elucidation of the mechanisms whereby the liver maintains glucose homeostasis is crucial for the understanding of physiologic and pathologic states. Here, we show a novel role of hepatic transcriptional co-activator with PDZ-binding motif (TAZ) in the inhibition of glucocorticoid receptor (GR). TAZ interacts via its WW domain with the ligand-binding domain of GR to limit the binding of GR to gluconeogenic gene promoters. Therefore, liver-specific TAZ knockout mice show increases in glucose production and blood glucose concentration. Conversely, the overexpression of TAZ in mouse liver reduces the binding of GR to gluconeogenic gene promoters and glucose production. Thus, our findings demonstrate distinct roles of the hippo pathway effector proteins yes-associated protein 1 (YAP) and TAZ in liver physiology: while deletion of hepatic YAP has little effect on glucose homeostasis, hepatic TAZ protein expression decreases upon fasting and coordinates gluconeogenesis in response to physiologic fasting and feeding.

In humans, type 2 diabetes progresses when beta-cells fail to compensate peripheral insulin resistance. Insulin receptor substrate (IRS) proteins mediate a variety of the metabolic and growth-promoting actions of insulin and IGF-1, and are important integrators of heterologous regulation. Systemic ablation of the Irs2 gene in mice causes β-cell dysfunction that prevents compensatory insulin secretion while insulin resistance progresses to life threatening hyperglycemia. Upregulation of IRS2 in pancreatic β-cell using rat insulin-2 promoter (Irs2^RIP) promotes sufficient hyperinsulinemia to prevent diabetes. Targeted Irs2 deletion using Cre^RIP also causes beta-cell failure and hyperglycemia, but the mechanism is unclear because Cre^RIP drives deletion in beta-cells and hypothalamus—especially in the arcuate nucleus (ARC). AGRP neurons in the ARC play an important role in regulating energy homeostasis, but it is unknown whether IRS2 in the AGRP neurons might also affect beta-cell function. Here we show that disruption of Irs2 (but not Irs1) in AGRP neurons (Irs2^f/fCre^Agrp-mice) reduced islet mass by 45%. To test insulin secretory function, we subjected mice to hyperglycemic clamps. The glucose infusion rate to maintain steady-state hyperglycemia decreased significantly. Moreover, insulin secretion failed to respond to L-arginine treatment in aged Irs2^f/fCre^Agrp-mice. Moreover, Irs2^f/fCre^Agrp-mice displayed progressive deterioration of glucose homeostasis and a lack of beta -cell compensation during high fat diet. Overall, our results indicate that dysfunction of Irs2 in AGRP neurons might contribute to the pathophysiology of type 2 diabetes. Disclosure R. Tao: None. K.D. Copps: None. M.F. White: Advisory Panel; Self; Housey Pharmaceutical Research Laboratories. O. Stoehr: None. Funding National Institutes of Health (5R01DK098655-06)

In the version of this article originally published, the y axis labels in Fig. 4b,d were incorrect. In Fig. 4b, the unit on the label was (ng mg–1). This should have been (ng/ml). In Fig. 4d, the y axis label was Serum Fst (ng ml–1). It should have been Serum insulin (ng/ml). The errors have been corrected in the HTML and PDF versions of this article.