Researching Metabolic Diseases
The etiology, pathogenesis, and treatment of metabolic diseases, including primarily obesity, NAFLD/NASH, diabetes, and their associated comorbidities, including cardiovascular diseases, strokes, and several malignancies. Our group works hard to
understand the mechanisms underlying these disorders, to prevent, diagnose
and treat these disease states by developing rational novel diagnostic and
therapeutic tools for these conditions.
Basic Research Studies
Our basic research studies focus on physiological and pathophysiological
regulation of novel molecules important in energy homeostasis, obesity, NASH, and diabetes,
and obesity, as well as complications of the latter including
cardiovascular disease and malignancies. We utilize a wide range of
research methods including genomics-bioinformatics, molecular biology, and
animal physiology studies to answer important questions regarding obesity,
insulin resistance, and their consequences which include diabetes,
cardiovascular disease, and malignancies. Our ultimate goal is to develop
novel diagnostic and therapeutic strategies by better-understanding and
exploiting underlying mechanisms. Our main focuses are:
Molecular pathogenesis of obesity, NASH, insulin resistance, and associated
comorbidities, including cancer, cardiovascular disease, insulin
resistance and type 2 diabetes
Molecular biology, physiology, and pathophysiology of adipokines, such
as leptin, adiponectin etc. in animals and humans
Molecular biology, physiology, and pathophysiology of hepatokinas, incretins, and myokines, in animals and humans
We conduct and participate in large-scale epidemiological investigations,
including cross-sectional, cohort, and case control studies, in
collaboration with members of the Environmental Health, Nutrition, and
Epidemiology Departments of the Harvard School of Public Health as well as
the Veterans Administration healthcare system and several major epidemiology universities and institutions worldwide, e.g. Karolinska Institutet and Uppsala University.
Our research efforts have expanded to studying non-modifiable disease
determinants, including certain single nucleotide polymorphisms, as well as
modifiable determinants, such as diet and exercise, as predictors of
adipokine concentrations and/or metabolic diseases.
Following our initial work on the role of insulin and insulin-like growth
factors, we performed the first case-control and prospective cohort studies
demonstrating that adiponectin is a key link between obesity/insulin
resistance and common malignancies associated with obesity including
endometrial, breast, prostate, renal, and colon cancers. Ongoing studies
are investigating the underlying mechanisms and exploring the roles of
adiponectin and other adipokines as diagnostic and therapeutic agents in
these disease states. We are also involved in Mendelian Randomization studies and disease trajectory studies.
The above basic research and epidemiologic studies have provided important
new information and have advanced our knowledge of human physiology and
pathophysiology. The hope is that these advances will ultimately lead to
Our main focuses are:
Clinical epidemiology studies in the areas of obesity, NAFLD / NASH, diabetes, cardiovascular disease, and malignancies.
- Raising and testing hypotheses of the physiological and pharmacological role of novel compounds.
Developing new diagnostic and therapeutic tools for the above disease
To understand the neuropharmacology underlying leanness and obesity, we
utilize functional magnetic resonance imaging and neurocognitive testing.
Our recent studies have illuminated the functional brain activation changes
to food cues in response to leptin administration in lean, hypoleptinemic
women. Studies examining the effects of other molecules, such as GLP-1 analogues, or
medications, such as lorcaserin, which treat obesity are underway.
Furthermore, we are also examining where receptors for key molecules
regulating energy homeostasis are expressed in the human brain using
immunohistochemistry and study their function using in vitro and in vivo
techniques. Through the combination of these techniques, we will be better
able to understand the mechanisms of action for these molecules and be
better able to help develop future, successful therapeutics.
Clinical Interventional Studies
Our interventional studies in humans range from early phase pharmacokinetic
and small scale, investigator-initiated "proof of concept" studies, to
medium, and large-scale double blind placebo-controlled clinical trials,
which, if positive, are later expanded into multi-center clinical trials.
Our group was the first to complete pharmacokinetic studies of leptin in
humans and were the first to conclusively demonstrate, utilizing "proof of
concept" studies involving leptin administration, the role of leptin in
regulating the neuroendocrine response to energy deprivation in humans. We
were also the first to demonstrate that low leptin levels are intimately
linked with neuroendocrine abnormalities observed in the "female triad" (a
disease state characterized by the simultaneous presentation of disordered
eating, amenorrhea, and decreased bone mineral density) or in anorexia
nervosa. Further, we demonstrated that administration of leptin, in
replacement doses, corrects neuroendocrine and reproductive abnormalities
and improves markers of bone density in strenuously exercising women
athletes with the "female triad". Leptin was recently approved by the FDA
for treatment of lipodystrophy in humans.
Currently, we are further exploring the role of leptin in the physiology,
pathophysiology, and potential treatment of several disease states,
Examples of our current studies are presented in the
Our work, funded by the NIH, the ADA, HMS, various foundations, and the pharmaceutical industry, has resulted in over 600 original publications in medicine, more than 150 collaborative papers in the context of the Look AHEAD Study, over 230 reviews/chapters in textbooks, which have received over 86,000 citations with an H-index of more than 147 in Google Scholar. Group members have been honored with numerous prestigious awards at national and international meetings.