NIDDK

Recent Advances & Emerging Opportunities

January 2024

Obesity

U.S. Department of Health and Human Services

National Institutes of Health

National Institute of Diabetes & Digestive & Kidney Diseases

This is a chapter from the NIDDK’s Annual Report. The full Report includes highlights of research on 

these and many other areas across the NIDDK’s mission and is available at: 

www.niddk.nih.gov/about-niddk/strategic-plans-reports/niddk-recent-advances-emerging-opportunities
Obesity TOC 2024

OBESITY ....................................................................47

Timing Meals to Improve Health.............................49



How Meal Timing May Reduce Obesity
 

and Improve Metabolic Health ........................49



Limiting Eating Times to Improve Health 

of People Who Work Around the Clock ........49



Examining the Effects of



Weight-Loss Surgeries ..............................................50



Weight-Loss Surgery That Reprograms 

the Body’s Internal Clock to Improve 

Metabolism and Eating Behavior ....................50



Substance Produced by Gut Following 

Bariatric Surgery Regulates Metabolic 

Health in Mice .....................................................50



Feature: Medications to Treat Obesity: 

Past, Present, and Future..........................................52



NIDDK Recent Advances & Emerging Opportunities 2024 
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 47

The NIH-wide Obesity Research Task Force was established to accelerate progress in obesity research across NIH, 

given the importance of the obesity epidemic as a major public health problem and its relevance to the missions of 

most of the NIH Institutes, Centers, and Offices. The Task Force is co-chaired by the Director of NIDDK, Dr. Griffin 

P. Rodgers; the Director of the National Heart, Lung, and Blood Institute, Dr. Gary H. Gibbons; and the Director of 

the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Dr. Diana W. Bianchi. The 

Task Force holds two seminars each year, covering a broad range of topics. On September 8, 2023, the Task Force 

convened a symposium on medications to treat obesity where seven distinguished scientists highlighted their research 

in this field, and two individuals who have used these medications shared their personal perspectives and experiences. 

A summary of this seminar is in this chapter.
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 48

The high prevalence of obesity in the United States 

is thought to result from the interaction of genetic 

susceptibility with behaviors and factors in the 

environment (social determinants of health) such as a 

lack of healthy, affordable food and places to exercise in 

many communities; sedentary jobs; and other conditions 

that influence what, when, and how much people eat. 

Diet, activity, and aspects of our environment also may 

modify biological factors in ways that promote obesity. 

Research is providing the foundation for actions to 

address this major public health problem by illuminating 

the causes and consequences of obesity, evaluating 

potential prevention and treatment strategies, and 

providing an evidence base to inform policy decisions. 

NIDDK supports a multidimensional research portfolio 

on obesity, spanning basic, clinical, and translational 

research. This research is coordinated through 

NIDDK’s Office of Obesity Research and supported 

by NIDDK’s Division of Diabetes, Endocrinology, and 

Metabolic Diseases and Division of Digestive Diseases 

and Nutrition. NIDDK-funded studies investigate 

a variety of approaches for preventing and treating 

obesity. These span behavioral and environmental 

interventions for children and adults in health care, 

home, community, and other settings using a variety of 

approaches and technologies, surgical interventions, 

and combinations of strategies. In parallel, NIDDKsupported investigations into the biologic processes 

associated with body weight have continued to spark 

new ideas for intervention approaches.

NIDDK also continues to play a leading role in the NIH 

Obesity Research Task Force. The NIDDK Director 

co-chairs the Task Force along with the Directors of 

the National Heart, Lung, and Blood Institute and the 

Eunice Kennedy Shriver National Institute of Child Health 

and Human Development. The Task Force includes 

representatives from these and numerous other NIH 

Institutes, Centers, and Offices to promote collaboration 

and enhance obesity research across NIH.

Obesity has risen to epidemic levels in the United States. Individuals who have obesity may 

develop devastating health problems, face reduced life expectancy, and experience stigma 

and discrimination. Obesity is a strong risk factor for type 2 diabetes, fatty liver disease, and 

many other diseases and disorders within NIDDK’s mission. Nearly 42 percent of U.S. adults 

are considered to have obesity based on body mass index (BMI), a measure of weight relative 

to height.1,2 Nearly 20 percent of children and adolescents also have obesity, and thus are at 

increased risk for developing serious diseases both during their youth and later in adulthood.1,3 

Obesity disproportionately affects people from certain racial and ethnic groups and those who 

are socioeconomically disadvantaged. 

Obesity

1

 Stierman B, et al. National Health and Nutrition Examination Survey 2017– 

March 2020 prepandemic data files—Development of files and prevalence 

estimates for selected health outcomes. Centers for Disease Control and 

Prevention. National Health Statistics Reports 158, 2021. 

2

Although higher BMI levels generally reflect higher levels of body fat on a 

population level, BMI does not directly measure body fat or take into consideration 

age, biological sex, or health risks of populations other than non-Hispanic White.

3

 For children and adolescents, obesity refers to a BMI at or greater than the 95th 

percentile on growth charts (which are based on previous national surveys).

Nearly 42 percent of U.S. adults and nearly 20 

percent of children and adolescents have obesity.

NIDDK supports basic, clinical, and 

translational research to discover how body 

weight is regulated and to design and evaluate 

approaches for preventing and treating obesity.
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 49

TIMING MEALS TO IMPROVE HEALTH

How Meal Timing May Reduce Obesity and Improve 

Metabolic Health: Scientists have revealed a 

mechanism behind why eating late at night can be 

linked to weight gain and metabolic disease in a study in 

mice. The connection between meal timing, sleep, and 

obesity is well known, but poorly understood. Research 

shows that eating during inactive periods (at night 

for people and during the day for nocturnal mice) can 

disrupt the body’s internal molecular “clock,” leading 

to an impairment of numerous physiological processes 

across the day/night cycle, including energy (calorie) 

intake and energy expenditure. This mistimed feeding 

can also alter fat tissue and contribute to weight gain. 

Understanding how meal timing affects metabolism 

could help the development of interventions for 

obesity.

To explore the reasons behind mistimed feeding and 

weight gain, researchers fed male mice a high-fat 

diet either exclusively during their inactive or their 

active period. Within 1 week, mice fed during their 

inactive period gained more weight and experienced 

decreased energy expenditure compared to those 

fed only in the active period, replicating what has 

been previously shown. This result led the team to 

investigate whether fat tissue metabolism differed 

based on the meal timing. Using mice that were 

genetically altered to have enhanced thermogenesis—

or heat released by fat cells burning calories—they 

found that the mice fed during the inactive period 

did not gain weight and had improved glucose 

(sugar) tolerance, a measure of metabolic health, 

compared to mice without enhanced thermogenesis 

fed the same food during the same time of day, 

suggesting that thermogenesis protects against 

weight gain resulting from inactive period meals. 

Next, they sought to determine the specific metabolic 

underpinnings of this protection and identified the 

molecule creatine, which the body stores to use as 

energy, as the likely metabolic mechanism through 

which restricting feeding to the active period 

improves health. Indeed, genetic disruption of 

creatine synthesis in fat cells reduced the metabolic 

benefits of feeding restricted to the active period. 

Taken together, these results expand upon our 

knowledge of the mechanisms that underlie the benefits 

of restricting eating to active periods. Time-restricted 

feeding in people is a promising approach to decrease 

body weight and improve metabolic health with few side 

effects. However, given that many people are unable to 

maintain this schedule for reasons including shift work, 

sleep loss, and the social aspect that people tend to 

dine in the evening, more research could help inform the 

design of behavioral and therapeutic interventions. 

Hepler C, Weidemann BJ, Waldeck NJ,...Bass J. Time-restricted feeding 

mitigates obesity through adipocyte thermogenesis. Science 378: 276-

284, 2022.

Limiting Eating Times to Improve Health of People 

Who Work Around the Clock: In a study to improve the 

health of people who do shift work, researchers found 

that time-restricted eating was feasible for firefighters 

on 24-hour schedules and led to cardiometabolic 

benefits, particularly for those who had health risks 

when the study began. Shift work disrupts cycles 

of sleeping, eating, and activity, and it is associated 

with cardiovascular and metabolic disease. Thus, the 

researchers developed an intervention to reduce these 

health risks while being compatible with shift-work 

schedules and the nature of firefighting work, and they 

tested this in a clinical trial.

The intervention focused on time-restricted eating (TRE), 

limiting calorie intake to a 10-hour window per day 

most days of the week for 12 weeks. As an innovative 

strategy to inform recruitment and other aspects of 

the study design, the researchers consulted with fire 

departments and related organizations and did a 24-hour 

ride-along to understand the participants’ shift-work 

lifestyle. The study participants, 137 firefighters working 

24-hour shifts, were recruited from a local fire-rescue 

department. Over 90 percent were male, reflecting 

the fire department’s demographics, and were from 

different racial groups and ethnicities; a majority were 

White though race was unknown for some participants. 

The researchers randomly assigned the participants to 

either the TRE group or a standard of care group. They 

advised both groups to follow a Mediterranean diet (e.g., 

Scientists have revealed a mechanism 

behind why eating at night can be linked to 

weight gain and metabolic disease.

Researchers found that time-restricted eating 

was feasible for firefighters on 24-hour shift 

work and led to health benefits for those with 

cardiometabolic risks.
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 50

eating more fruits and vegetables, olive oil, and fish); 

collected thousands of time-stamped food and beverage 

records, which the firefighters logged using an app on 

their smartphones; and examined health measures. The 

results showed that TRE was feasible, as the firefighters 

in the TRE group reduced their eating time from around 

14 hours per day when the study began to about 

11 hours per day. Among the subset of participants 

who had elevated risk factors before the intervention 

began, those in the TRE group had improved blood 

glucose (sugar) and diastolic blood pressure by the end 

of the study, compared to the standard of care group. 

Among all the participants, those in the TRE group had 

improvements in a blood lipid, VLDL, and better quality 

of life measures compared to the standard of care group. 

Some health improvements were seen in both groups 

(e.g., systolic blood pressure), possibly associated with 

dietary changes. No adverse events were reported. 

These encouraging results show health benefits of timerestricted eating for people doing shift work and open 

the way to potential future studies with larger numbers 

of participants, including more women, and that explore 

longer-term health effects. 

Manoogian ENC, Zadourian A, Lo HC,...Panda S. Feasibility of timerestricted eating and impacts on cardiometabolic health in 24-h shift 

workers: the Healthy Heroes randomized control trial. Cell Metab 34: 

1442-1456.e7, 2022.

EXAMINING THE EFFECTS 

OF WEIGHT-LOSS SURGERIES

Weight-Loss Surgery That Reprograms the Body’s 

Internal Clock to Improve Metabolism and Eating 

Behavior: Scientists studying gastric bypass surgery, a 

treatment for severe obesity that also ameliorates 

type 2 diabetes, discovered that, in mice, this surgery 

reprograms the biological day/night “clock” to adjust the 

timing and amount of food consumption and improve 

glucose (sugar) metabolism. In designing the study, they 

sought to explore a potential connection between weightloss surgery and the body’s innate molecular clock based 

on previous research. Past studies showed that this clock 

synchronizes metabolism, eating, and other processes 

with 24-hour day/night cycles, and that risks for obesity 

and type 2 diabetes increase when day/night cycles are 

disrupted, for example, when people do shift work. 

For their study, the researchers compared mice that had 

Roux-en-Y gastric bypass (RYGB) surgery to those of 

similar body weight that did not have the surgery, with 

both groups on a high-fat diet. While a high-fat diet 

typically alters the amount and timing of food intake 

in mice, those that had RYGB surgery ate less overall 

and shifted more of their food consumption to the time 

in the day/night cycle when mice normally eat. The 

researchers then analyzed different tissues for potential 

effects on genes encoding clock functions, which exist 

throughout the body, and found that RYGB surgery led 

to changes in the activity of clock genes in the liver, 

an organ with important roles in glucose metabolism. 

To further test the relevance of the clock to surgical 

outcomes, they examined mice that lacked a key clock 

gene. They discovered that, compared to other mice, 

the clock-deficient mice lost less weight after RYGB 

surgery and did not have improvements in glucose 

metabolism. Thus, a functional clock was needed for 

these beneficial effects. 

This study in mice demonstrates the role of the body’s 

molecular clock in weight loss, eating times, and 

glucose metabolism after RYGB surgery for obesity. If 

the molecular clock has a similar role in RYGB surgical 

outcomes in humans, researchers could study whether 

adjusting meal and snack times may yield more health 

benefits. Further research on the effects of different 

bariatric (weight loss) surgical procedures could also lead 

to new, less invasive treatment approaches.

Ye Y, Abu El Haija M, Obeid R,...Mokadem M. Gastric bypass alters diurnal 

feeding behavior and reprograms the hepatic clock to regulate endogenous 

glucose flux. JCI Insight 8: e166618, 2023.

Substance Produced by Gut Following Bariatric Surgery 

Regulates Metabolic Health in Mice: New research in mice 

has identified a key player produced by the gut that links 

surgical and dietary weight-loss therapies to improvements 

in metabolic and digestive health. Interventions such as 

bariatric surgery or a high-fiber diet can protect against the 

development of metabolic diseases like type 2 diabetes. 

Some health benefits from bariatric surgery can even occur 

independently from weight loss, although exactly how this 

happens is not clear. Further research on mechanisms 

underlying these effects may one day lead to new ways to 

treat metabolic diseases.

A substance produced by the gut called Reg3g 

is important for conferring improvements 

in metabolic and digestive health following 

bariatric surgery.
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 51

Reg3g is an antimicrobial peptide (a mini version of 

a protein) produced in the small intestine to help 

prevent resident bacteria from invading the intestinal 

wall. Because previous studies have shown that Reg3g 

confers health benefits in addition to its antibacterial 

properties, the researchers sought to examine whether 

Reg3g can also contribute to the health effects of 

bariatric surgery or a high-fiber diet and offer protection 

against metabolic diseases like type 2 diabetes. The 

researchers found that levels of Reg3g ramp up in 

mice after a type of bariatric surgery called vertical 

sleeve gastrectomy (VSG). To determine if Reg3g was 

responsible for the beneficial metabolic effects of VSG, 

the researchers performed VSG on male mice that were 

genetically altered to lack Reg3g. When compared to 

normal mice, the mice lacking Reg3g slowly regained 

weight and did not show improvements in blood glucose 

(sugar) levels and insulin production, implicating Reg3g 

in weight loss maintenance and better metabolic health 

after bariatric surgery. The researchers also saw 

improved metabolic health when they administered 

Reg3g to mice who did not undergo surgery, pointing 

to a possible role for Reg3g in protection against 

type 2 diabetes. When the researchers looked at the 

microbiome (the community of microbes in the gut) 

following VSG or a high-fiber diet, they found that 

these interventions changed the composition of the 

microbiome by boosting levels of certain beneficial 

bacteria, which in turn stimulated Reg3g production. 

Furthermore, Reg3g was found to play an important role 

in improving gut function, such as strengthening the gut 

barrier and reducing cellular stress in the small intestine. 

These results suggest that changes to the microbiome 

due to bariatric surgery or a high-fiber diet stimulate 

production of Reg3g, which in turn mediates a variety of 

health benefits. Interestingly, the researchers also found 

that Reg3g is elevated following VSG in young people 

with obesity. If Reg3g causes similar metabolic effects 

in humans as in mice, it could mean that Reg3g-based 

treatments might have therapeutic value for people with 

metabolic diseases like type 2 diabetes.

Shin JH, Bozadjieva-Kramer N, Shao Y,...Seeley RJ. The gut peptide Reg3g 

links the small intestine microbiome to the regulation of energy balance, 

glucose levels, and gut function. Cell Metab 34: 1765-1778, 2022.
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 52

FEATURE

Medications to Treat Obesity: 

Past, Present, and Future

The epidemic of obesity continues to rise in the United 

States in adults and children. Obesity increases risk 

for diseases and conditions such as type 2 diabetes, 

cardiovascular disease, and some types of cancer 

and cancer-related death, and it also complicates the 

management of a myriad of diseases. While enormous 

progress has been made in the pharmacological 

management of diseases and conditions closely 

integrated with excess body weight, such as 

hypertension and type 2 diabetes, the treatment of 

obesity itself has proven largely resistant to therapy, 

with anti-obesity medications of the past often 

delivering insufficient efficacy and safety concerns 

that limited use and resulted in the removal of drugs 

from the market. While lifestyle and behavioral 

interventions help many people lose weight, some 

people cannot lose enough weight to improve health 

with lifestyle treatments alone, and even among those 

who do, weight loss is often difficult to maintain. 

Recent advances are now inspiring the pursuit of 

next-generation anti-obesity medications that appear 

capable of safely achieving significant and sustained 

body weight loss. With increasing knowledge, there 

is real potential to vastly expand therapeutic options 

for obesity treatment, allowing for more personalized 

and effective approaches to care. To that end, seven 

leading scientists highlighted their research at a 

September 2023 symposium organized as part of the 

NIH Obesity Research Task Force Seminar Series. 

The research presented was supported by NIDDK, 

other NIH Institutes, and other sources. 

Dr. Matthias Tschöp of the German research center 

Helmholz Zentrum München presented an overview 

of obesity drug development ranging from diet pills 

of the past up to the current transformative era of 

obesity pharmacotherapies capable of safely inducing 

substantial amounts of weight loss. One class of 

medications that is particularly promising for the 

management of obesity is incretin-based therapies. 

Incretins are hormones secreted by the gut in response 

to food ingestion, which then regulate blood glucose 

(sugar) and delay stomach emptying, but also have 

effects on multiple other organs, including the brain. 

Medications that mimic these hormones have been 

approved by the U.S. Food and Drug Administration 

(FDA) for the treatment of type 2 diabetes for more 

than a decade, but due to their significant effects 

on body weight, some have also been approved for 

obesity treatment. Some of the new medications 

lead to weight losses approaching those seen with 

bariatric surgery, and recent preliminary data suggest 

they may also reduce the risk of cardiovascular disease 

and death for some people with obesity. Additional 

medications are in the research and development 

pipeline, including hormones targeting multiple 

receptors and combination therapies, with a goal of 

increasing efficacy while minimizing adverse effects. 
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 53

FEATURE

Dr. Randy Seeley of the University of Michigan 

presented his research on the mechanisms by which 

incretin-based drugs work in the brain to treat obesity. 

He described the concept of a “set point,” a term that 

describes a weight range the body strives to maintain, 

and one which is elevated in a setting of obesity. The 

set point is regulated by key hormones that act in the 

brain and by genetics, as well as by calorie intake and 

expenditure, and it provides a potential explanation for 

why it can be difficult for people on a diet to maintain 

weight loss over time as the body is driven back 

toward a predetermined set point. Through a series 

of experiments in rodents, Dr. Seeley showed that 

overfeeding or calorie restriction will expectedly cause 

weight gain or loss, respectively. However, when the 

animals returned to eating normally, they very quickly 

returned to their set point. He went on to show that 

when rodents were administered obesity medications 

that target the brain, their set points appeared to 

become lower, leading to substantial weight loss that 

was maintained while receiving the drug.

Dr. Domenica Rubino of the Washington Center for 

Weight Management and Research presented her 

research on the incretin-based drug semaglutide for 

obesity treatment in adults through the Semaglutide 

Treatment Effect in People with obesity (STEP) 

clinical trials. The STEP program evaluates the safety 

and efficacy of semaglutide in a diverse population 

of adults with obesity and with or without type 2 

diabetes. Semaglutide resulted in significant and 

sustained weight loss of 15 to 20 percent of body 

weight. In addition, the treatment improved cardiac 

risk factors such as blood pressure, reduced blood 

glucose levels, and decreased incidence of fatty 

liver. Participants reported improvements in healthrelated quality of life and a better sense of control 

over cravings, along with well-tolerated, primarily 

gastrointestinal side effects such as nausea, which can 

be affected by adjusting the dose. Evidence thus far 

supports the efficacious and safe use of semaglutide 

for weight management in adults with obesity. 

Dr. Ania Jastreboff of Yale University School of 

Medicine presented her research on the incretinbased drug tirzepatide for obesity treatment in 

adults, and she also provided a glimpse at new 

medications in the drug development pipeline. In 

a randomized, controlled clinical trial that enrolled 

more than 2,500 participants, nearly all participants 

lost weight while taking tirzepatide, while close to 

half of those lost more than 25 percent of their body 

weight. Participants on tirzepatide had a greater 

percent reduction in fat body mass than lean body 

mass, resulting in an overall improvement in body 

composition. Furthermore, of the participants 

who had prediabetes, nearly all reverted to normal 

blood glucose levels while taking tirzepatide, and 

cardiometabolic measures such as blood pressure 

improved. Participants taking the medication reported 

mild to moderate gastrointestinal adverse effects, 

and thus there is a need to titrate the dose for each 

patient. The efficacy, tolerability, and safety profiles 

of tirzepatide appear consistent with those of similar 

anti-obesity medications. Dr. Jastreboff previewed 

several new incretin-based and small molecule drugs 

currently in phase 2 and 3 clinical trials in the drug 

development pipeline. 

Dr. Jack Yanovski of the Eunice Kennedy Shriver 

National Institute of Child Health and Human 

Development at NIH highlighted his research 

on medications for the treatment of obesity in 

children and adolescents and gave an overview of 

the field. There are currently five FDA-approved 

drugs to treat obesity in children aged 12 to 16 

years and one medication approved for children 

under age 12 years. Several approved medications 

to treat obesity in youth have limited efficacy and 

are associated with adverse side effects that could 

impede adherence. However, the same incretinbased drugs that work well in adults appear effective 

for weight reduction in adolescents when combined 

with lifestyle modification. Dr. Yanovski noted that 

highly effective approaches currently being studied 

in adults with obesity represent a treatment gap 

for children, especially for those under the age of 

12 years. More research is necessary to gain a 

greater understanding of the biology of why obesity 

medications do not work for some youths, and a 

prime focus of research should also be to develop 

effective prevention strategies. 
NIDDK Recent Advances & Emerging Opportunities 2024: Obesity 54

FEATURE

Dr. Louis Aronne of Weill Cornell Medicine presented 

his work on using medications to treat obesity in 

clinical practice. He described key principles to 

prescribing medication to treat obesity such as 

considering the patient’s severity of disease, any 

comorbidities that may require medications that cause 

weight gain, potential adverse side effects and how to 

manage them, and affordability of the treatment. 

Dr. Aronne stressed the importance of an individualized, 

multipronged, stepwise approach. For example, 

the clinician should start a patient on a low dose of 

medication and slowly increase to assess tolerability 

and efficacy; if one medication is not effective, switch 

to another; and combination therapies can be evaluated 

to improve results. Dr. Aronne also highlighted case 

studies from his clinic that illustrate effective use of 

anti-obesity medications. 

Dr. Ilhuoma Eneli of Children’s Hospital Colorado 

presented research on access to obesity treatment 

and health equity. She described how disparities and 

inequity contribute to obesity through historical, social, 

economic, and policy contexts that have systematic 

effects on weight-related outcomes. Health carerelated factors that drive disparities include the often 

high cost of treatment; location of treatment centers, 

with many in large, urban areas, limiting access to rural 

populations; access to insurance; inadequate provider 

training; suboptimal diagnostic criteria that may not 

reflect health risks across different populations (e.g., 

Asian American populations); and bias/stigma. A 

related factor is insufficient diversity in clinical trials. 

Dr. Eneli discussed potential solutions to address 

structural and systemic factors that lead to inequity 

in obesity treatment, such as policy change to ensure 

affordable and accessible options for all. Solutions 

remain complex and nuanced, and they must occur at 

the individual, community, and structural levels and 

in health care environments to effectively address 

inequities as they pertain to obesity prevention and 

treatment strategies. 

The seminar concluded with a panel discussion 

featuring two women with experience using obesity 

medications who shared their personal perspectives. 

Following their poignant testimonies, they were 

joined on the panel by the scientific speakers for 

a lively discussion with participants, moderated by 

Dr. Susan Yanovski, NIDDK, on current challenges 

and opportunities in this evolving landscape of 

transformative obesity medicine. Continued research 

could reveal better strategies to prevent and treat 

obesity with personalized approaches to improve 

health care for all.