Treating obesity by activating beige and brown fat; human transplant studies

Summary

Obesity occurs when energy intake exceeds energy expenditure. Current treatments for obesity are largely ineffective, and two-thirds of Australian adults are now overweight or obese.

Rodents and hibernating animals like bears and Siberian Hamsters are known to possess significant quantities of brown adipose tissue (BAT), a specialised organ that can generate heat in response to cold exposure. This thermogenic property is conferred upon BAT by a unique protein; uncoupling protein 1 (UCP1). When activated, UCP1 allows brown fat cells to generate heat. When cold-adapted activated BAT can burn more energy than any other organ in the body (per gram of weight), much more than the heart or skeletal muscle.

Recent advances in metabolic imaging have shown that most human adults possess at least some BAT. Although these deposits are quite small (<50g), it has been estimated that activation of BAT could increase resting daily energy expenditure by up to 20%. BAT could be used to improve blood glucose (diabetes) and lipids in the circulation of overweight or obese people.

Independently of BAT, fat cells (adipocytes) identical to those in BAT have also been identified in depots of white adipose tissue (WAT). WAT is the largest type of adipose tissue in humans and mammals. Under certain conditions, such as cold exposure or stimulation of the sympathetic nervous system, a proportion of the adipocytes in WAT can be converted into brown-like ('beige' or 'brite') adipocytes that are capable of generating heat. These beige/brite adipocytes protect against obesity, however, their specific contribution to overall energy balance and metabolism isn't known.

Our overall aim is to remodel fat, especially WAT to treat obesity and help glucose intolerance, diabetes and insulin resistance. Beige/brite adipocytes represent an important therapeutic target for drugs that could increase resting energy expenditure.

Supervisor(s)

Professor Jenny Gunton

Research Location

Westmead - Westmead Institute for Medical Research

Program Type

PHD

Synopsis

The aim of this project is to investigate agents which may increase browning or beiging of human fat.

This project will determine the whole-body effects of browning agents on energy balance and glucose and fat handling (metabolism) in mice which have receive human fat transplants.

These experiments will involve pharmacological treatment of mice, measurement of glucose/lipid metabolism, measurement of energy metabolism at the whole-body and tissue levels. We will also be using lentivirally-delivered shRNA to silence the expression of genes in adipocytes and adipose tissue.

Techniques will also involves using the Seahorse Bioanalyser, Prometheon Metabolic cages, RNA-Sequencing, Real-time PCR, histology and a range of othersThe aim of this project is to investigate agents which may increase browning or beiging of human fat.

Additional Information

Westmead Institute for Medical Research has a ‘top-up' award program for students who are successful in obtaining a scholarship (e.g. Research Training Award).

Some recent publications include:

Lee P, Swarbrick MM, Greenfield JR. The sum of all browning in FGF21 therapeutics [Commentary]. Cell Metabolism 2015;21(6):795-6.

Hocking SL, Stewart RL, Brandon AE, Suryana E, Stuart E, Baldwin EM, Kolumam GA, Modrusan Z, Jununtula JR, Gunton JE, Medynskyj M, Blaber SP, Karsten E, Herbert BR, James DE, Cooney GJ, Swarbrick MM. Subcutaneous fat transplantation alleviates diet-induced glucose intolerance and inflammation in mice. Diabetologia 2015;58(7):1587-600.

Swarbrick MM. A lifetime on the hips: programming lower-body fat to protect against metabolic disease [Commentary]. Diabetes 2014; Nov;63(11):3575-7.

Petruzzelli M, Schweiger M. Schreiber R, Campos-Olivas R, Tsoli M, Allen J, Swarbrick MM, Rose-John S, Rincon M, Robertson G, Zechner R, Wagner EF. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metabolism 2014; 20:1-15.

Lee P, Swarbrick MM, Ho KKY. Brown adipose tissue in humans - a metabolic renaissance. Endocrine Reviews 2013; 34: 413-438.

Lee P, Swarbrick MM, Zhao JT, Ho KKY. Inducible brown adipogenesis in adult humans: culture of adipose precursor cells from human supraclavicular brown adipose tissue. Endocrinology 2011; 152: 3597-3602.

Lee P, Zhao JT, Swarbrick MM, Gracie G, Bova R, Greenfield JR, Freund J, Ho KKY. High prevalence of brown adipose tissue in adult humans. Journal of Clinical Endocrinology and Metabolism 2011; 96: 2450-2455.

Hoehn K, Turner N, Swarbrick MM, Wilks D, Preston E, Phua YW, Larance M, Hegarty BD, Pickford R, Hoy AJ, Kraegen EW, James DE, Cooney GJ. Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole-body energy expenditure or adiposity. Cell Metabolism 2010; 11(1): 70-76.

Want to find out more?

Contact us to find out what’s involved in applying for a PhD. Domestic students and International students

Contact Research Expert to find out more about participating in this opportunity.

Browse for other opportunities within the Westmead - Westmead Institute for Medical Research .

Keywords

Obesity, adipose tissue, glucose intolerance, Type 2 diabetes, Insulin resistance, transplantation, gene expression, thermogenesis, primary culture, shRNA, lentivirus human, transplant

Opportunity ID

The opportunity ID for this research opportunity is: 2250

Other opportunities with Professor Jenny Gunton