Takahisa Nakamura, PhD

Nakamura continues to make seminal contributions to our understanding of the role of the liver in the development of IR/T2D and the mechanism of bariatric surgery, one of the most effective therapy for obesity and IR/T2D. Nakamura demonstrated that Argonaute 2 (Ago2), a key regulator of miRNA-mediated RNA silencing, regulates systemic carbohydrate metabolism. Specifically, inactivation of liver-specific Ago 2 results in two findings: 1) A reduction in miRNAs known to impair glucose metabolism; and 2) An improvement in insulin sensitivity and glucose metabolism.

Nakamura discovered that bariatric surgery improves systemic carbohydrate metabolism, at least in part, by suppressing Ago2 slicer activity. The latter leads to reduced expression of the Ago2-dependent pathologic miRNAs and improves glucose metabolism in an Ago2 dependent manner. These findings suggest that: 1) Hepatic Ago2 deficiency resembles the effect of bariatric surgery in improving glucose metabolism; and 2) Beneficial effect of bariatric surgery is blunt in liver-specific Ago2-deficient mice. Thus, suppressing Ago2 may be a key component of the beneficial outcome of bariatric surgery.

Nakamura’s research focuses on the role of hepatocyte-derived extracellular vesicles (EVs) that include exosomes carrying RNAs in the pathogenesis of T2D. Recently, Dr. Nakamura discovered that EVs secreted from hepatocytes under stress conditions become pathogenic and induce abnormal inflammatory responses in immune cells such as monocytes and macrophages. Importantly, Nakamura’s work also suggests that anti-diabetic drug metformin, known to exert anti-inflammatory effects, attenuates the inflammatory trait of hepatocyte-derived EVs.

Philippe Backeljauw, MD

In this Novo Nordisk Research Foundation funded study Backeljauw, UC Department of Pediatrics professor, and Gajan Muthuvel, MD, clinical fellow, and colleagues evaluate the efficacy and safety of recombinant human growth hormone (rhGH) for the treatment of growth failure in children with aggrecan deficiency. Aggrecan is a proteoglycan, encoded by the ACAN gene, in which mutations result in altered growth plate morphogenesis and compromised long bone growth. RhGH treatment of this aggrecan deficient cohort was well tolerated with a beneficial impact on height SDS. All patients continue therapy in an extension trial. In an overlapping phenotyping study, researched described osteochondritis dissecans and early-onset osteoarthritis in a subset of 22 patients from nine families with this disorder. There is belief that aggrecan deficiency is an under-recognized disorder and that patients can present in endocrine and genetic clinics, as well as in orthopedic and rheumatology settings.

Halley Wasserman, MD, MS, CCD

Primary ovarian insufficiency, sometimes thought of as “early menopause”, impacts approximately one in every 10,000 young women before age 20 years. The resulting estrogen deficiency occurs at an interval of time critical for bone, cardiovascular and reproductive health. In addition, estrogen may play a role in the cognitive “brain fog” reported by some adult women going through menopause. There is not much known about the impact of this diagnosis on adolescents nor about the effects of estrogen replacement therapy on bone health, body composition, cognition, and health-related quality of life in teenagers. With support from the Patty Brisban Foundation, we are conducting a pilot study aimed at describing the presentation of this condition in adolescent women and assessing how treatment affects these multiple health outcomes. The information gained from this cohort may apply to adolescents and young women with estrogen deficiency in other clinical settings as well as provide new insights on management of the natural menopause that occurs in all women later in life.

Halley Wasserman, MD, MS, CCD

Healthy bone formation is critical during childhood and adolescence to limit the risk of fragility fractures and osteoporosis during adulthood. Weight-bearing activity is a key driver of bone formation during the pediatric years and studies have shown that children with limited mobility are at increased risk for impaired bone health and fragility fractures compared to healthy peers. Sclerostin, an inhibitor of bone formation, regulated by weight bearing activity and sensed by bone cells is a novel target for osteoporosis treatment in adults. In this study supported by the Shubert Research Center’s Clinical Research Feasibility Fund, we will correlate serum sclerostin levels with degree of gross motor function impairment in a cohort of prepubertal children with cerebral palsy and compare to healthy controls. Using dual energy x-ray absorptiometry (DXA) to assess bone density, we will elucidate the relationship between serum sclerostin, bone mass and mobility gathering important preliminary data to support future work on treatment of pediatric disuse osteoporosis.

Amy Sanghavi Shah, MD, and Mark DiFrancesco, PhD

The rates of type 2 diabetes in teens continues to rise and are the direct result of the obesity epidemic. There is a desperate need for studies dedicated to children with type 2 diabetes as childhood onset type 2 diabetes (T2D) differs dramatically from type 2 diabetes in adults making extrapolation of adult data impossible. Type 2 diabetes in youth has a more insidious onset, poorer response to medications, rapid progression to insulin dependence, and a risk of multisystem complications by early adulthood. Our team documented the effects of type 2 diabetes on peripheral vasculature and the heart. Now in a new NIH-funded study will evaluate whether these youth are at risk for vascular disease that extends to their brains. Using advanced magnetic imaging resonance (MRI) methods, this project will comprehensively determine what kind of impairment happens to the structure and function of blood vessels in the brain in teens type 2 diabetes and how that might lead to tissue loss and cognitive problems. This new knowledge will drive optimal design of treatment approaches to prevent or reverse brain complications that could otherwise extend to adulthood.

Amy Sanghavi Shah, MD

Plaque buildup (or the development of atherosclerosis) begins when low-density lipoproteins (LDL) enter the blood vessels around the heart and remain there. Data from our laboratory show high-density lipoproteins (HDL) have the ability to inhibit LDL entry and retention, the initial steps of atherosclerosis. In a recently funded NIH study, the Shah laboratory aims to define how the balance between LDL and HDL influences plaque buildup in the artery wall and how type 2 diabetes alters it. Specific studies focus on whether certain types of LDL are more likely to enter the vessel wall and whether there are certain types of HDL that are best at preventing LDL entry and retention. These results have the potential to inform future therapeutic strategies to block atherosclerosis initiation which currently do not exist. This work has the potential to benefit both youth and adults, and particularly individuals with type 2 diabetes who are at accelerated risk for cardiovascular disease.

Juan Sanchez-Gurmaches, PhD

Sanchez-Gurmaches continues to further our understanding of the developmental heterogeneity of adipocyte progenitors. In the past year, Sanchez-Gurmaches began using a new CRISPR mediated, time-resolved lineage tracing genetic system that allows for simultaneous interrogation of lineage history and transcriptomic information of tissues and single cells. By monitoring the CRISPR generated barcode sequences, this system allows for lineage reconstruction of any and all cells in the mouse body allowing for comparisons between cell types. In addition, Sanchez-Gurmaches discovered that Insulin/Akt signaling regulates the activity of the transcription factor ChREBP in adipocyte differentiation and metabolism. Sanchez-Gurmaches established ChREBP loss of function mouse models in adipocyte progenitors and mature adipocytes to study the contribution of ChREBP controlled transcription in brown and white adipocyte biology.

Nancy Crimmins, MD, Juan Sanchez-Gurmaches, PhD, Samantha Brugmann, PhD, Nicole Weaver, MD

Crimmins, a clinician in the Division of Endocrinology; Sanchez-Gurmaches, a basic scientist in division studying adipose tissue development; Brugmann, a basic scientist in the Division of Developmental Biology studying function of primary cilia on craniofacial development; and Weaver, a clinician researcher in the Division of Human Genetics, are collaborating on a project attempting to identify genes that cause early-onset severe obesity in toddlers and children < 5 years of age. Through this study they anticipate gaining a deeper understanding of basic mechanisms of adipose tissue growth and the role of cilia in the onset of obesity. These insights will provide novel avenues for the development of therapeutic tools against obesity.